Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: A new family of gerosuppressant agents

Cell Cycle

Volumn 12, Issue 4, 2013, Pages 555-578

  Menendez, Javier A ^a,b   Joven, Jorge ^c   Aragonès, Gerard ^c   Barrajón Catalán, Enrique ^d   Beltrán Debón, Raúl ^c   Borrás Linares, Isabel ^e,f   Camps, Jordi ^c   Corominas Faja, Bruna ^a,b   Cufí, Sílvia ^a,b   Fernández Arroyo, Salvador ^e,f   Garcia Heredia, Anabel ^c   Hernández Aguilera, Anna ^c   Herranz López, María ^d   Jiménez Sánchez, Cecilia ^e,f   López Bonet, Eugeni ^b,g   Lozano Sánchez, Jesús ^e,f   Luciano Mateo, Fedra ^c   Martin Castillo, Begoña ^a,b   Martin Paredero, Vicente ^c   Pérez Sánchez, Almudena ^d   Oliveras Ferraros, Cristina ^a,b   Riera Borrull, Marta ^c   Rodríguez Gallego, Esther ^c   Quirantes Piné, Rosa ^e,f   Rull, Anna ^c   Tomás Menor, Laura ^d   Vazquez Martin, Alejandro ^a,b   Alonso Villaverde, Carlos ^c   Micol, Vicente ^d   Segura Carretero, Antonio ^e,f   more..

^a CATALAN INSTITUTE OF ONCOLOGY   (Spain)

^b GIRONA BIOMEDICAL RESEARCH INSTITUTE IDIBGI   (Spain)

^c INSTITUT D INVESTIGACIÓ SANITÀRIA PERE VIRGILI IISPV   (Spain)

^d MIGUEL HERNÁNDEZ UNIVERSITY   (Spain)

^e UNIVERSITY OF GRANADA   (Spain)

^f Research and Development of Functional Food Centre (CIDAF)   (Spain)

^g HOSPITAL JOSEP TRUETA   (Spain)

Author keywords

Aging; AMPK; Cancer; Gerogenes; Gerosuppression; Hormesis; MTOR; Olive oil; Resveratrol; Xenohormesis

Indexed keywords

ADENYLATE KINASE; CURCUMIN; DECARBOXYMETHYL OLEUROPEIN AGLYCON; GROWTH ARREST AND DNA DAMAGE INDUCIBLE PROTEIN 45; LACTATE DEHYDROGENASE; MAMMALIAN TARGET OF RAPAMYCIN; METFORMIN; OLEUROPEIN AGLYCON; OLIVE OIL; POLYPHENOL; PROTEIN C FOS; QUERCETIN; RAPAMYCIN; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; RESVERATROL; SECOIRIDOID; SIRTUIN 1; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG;

AGING; ANTINEOPLASTIC ACTIVITY; ANTIOXIDANT ACTIVITY; CAENORHABDITIS ELEGANS; CANCER STEM CELL; ENDOPLASMIC RETICULUM STRESS; HORMESIS; HUMAN; OXIDATIVE STRESS; PLANT STRESS; PROTEIN UNFOLDING; REVIEW; XENOHORMESIS;

EID: 84874627322     PISSN: 15384101     EISSN: 15514005     Source Type: Journal    
DOI: 10.4161/cc.23756     Document Type: Review

References (355)

1. Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov 2005; 4:206-20; PMID:15729362; http://dx.doi. org/10.1038/nrd1657
2. McChesney JD, Venkataraman SK, Henri JT. Plant natural products: back to the future or into extinction? Phytochemistry 2007; 68:2015-22; PMID:17574638; http://dx.doi.org/10.1016/j.phytochem. 2007.04.032
3. Molinari G. Natural products in drug discovery: present status and perspectives. Adv Exp Med Biol 2009; 655:13-27; PMID:20047031; http://dx.doi. org/10.1007/978-1-4419-1132-2-2
4. Li JW, Vederas JC. Drug discovery and natural products: end of an era or an endless frontier? Science 2009; 325:161-5; PMID:19589993; http://dx.doi. org/10.1126/science.1168243
5. Lévesque H, Lafont O. Aspirin throughout the ages: a historical review. Rev Med Interne 2000; 21(Suppl 1):8s-17s; PMID:10763200
6. Vane JR. The fight against rheumatism: from willow bark to COX-1 sparing drugs. J Physiol Pharmacol 2000; 51:573-86; PMID:11192932
7. Hedner T, Everts B. The early clinical history of salicylates in rheumatology and pain. Clin Rheumatol 1998; 17:17-25; PMID:9586674; http://dx.doi. org/10.1007/BF01450953
8. Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science 2012; 336:918-22; PMID:22517326; http://dx.doi.org/10.1126/ science.1215327
9. Hardie DG, Ross FA, Hawley SA. AMP-activated protein kinase: a target for drugs both ancient and modern. Chem Biol 2012; 19:1222-36; PMID:23102217; http://dx.doi.org/10.1016/j.chembiol. 2012.08.019
10. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 2012; 13:251-62; PMID:22436748; http://dx.doi.org/10.1038/nrm3311
11. Xu J, Ji J, Yan XH. Cross-talk between AMPK and mTOR in regulating energy balance. Crit Rev Food Sci Nutr 2012; 52:373-81; PMID:22369257; http://dx.doi.org/10.1080/10408398.2010.500245
12. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 2012; 11:230-41; PMID:22186033; http://dx.doi. org/10.1016/j.arr.2011.12.005
13. Mousa SA, Gallati C, Simone T, Dier E, Yalcin M, Dyskin E, et al. Dual targeting of the antagonistic pathways mediated by Sirt1 and TXNIP as a putative approach to enhance the efficacy of anti-aging interventions. Aging (Albany NY) 2009; 1:412-24; PMID:20195491
14. Lee JH, Bodmer R, Bier E, Karin M. Sestrins at the crossroad between stress and aging. Aging (Albany NY) 2010; 2:369-74; PMID:20606249
15. Vakana E, Platanias LC. AMPK in BCR-ABL expressing leukemias. Regulatory effects and therapeutic implications. Oncotarget 2011; 2:1322-8; PMID:22249159
16. Steelman LS, Chappell WH, Abrams SL, Kempf RC, Long J, Laidler P, et al. Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging (Albany NY) 2011; 3:192-222; PMID:21422497
17. Del Barco S, Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, et al. Metformin: multi-faceted protection against cancer. Oncotarget 2011; 2:896-917; PMID:22203527
18. Leontieva OV, Blagosklonny MV. Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression. Aging (Albany NY) 2011; 3:1078-91; PMID:22156391
19. Calvanese V, Fraga MF. SirT1 brings stemness closer to cancer and aging. Aging (Albany NY) 2011; 3:162-7; PMID:21307403
20. Menendez JA, Cufí S, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Vellon L, et al. Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer. Aging (Albany NY) 2011; 3:1063-77; PMID:22170748
21. Pardo PS, Boriek AM. The physiological roles of Sirt1 in skeletal muscle. Aging (Albany NY) 2011; 3:430-7; PMID:21483036
22. Corominas-Faja B, Quirantes-Piné R, Oliveras-Ferraros C, Vazquez-Martin A, Cufí S, Martin-Castillo B, et al. Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. Aging (Albany NY) 2012; 4:480-98; PMID:22837425
23. Iglesias-Bartolome R, Gutkind SJ. Exploiting the mTOR paradox for disease prevention. Oncotarget 2012; 3:1061-3; PMID:23165441
24. Timmers S, Auwerx J, Schrauwen P. The journey of resveratrol from yeast to human. Aging (Albany NY) 2012; 4:146-58; PMID:22436213
25. Richardson RB. Ionizing radiation and aging: rejuvenating an old idea. Aging (Albany NY) 2009; 1:887-902; PMID:20157573
26. Calabrese EJ. Hormesis is central to toxicology, pharmacology and risk assessment. Hum Exp Toxicol 2010; 29:249-61; PMID:20332169; http://dx.doi. org/10.1177/0960327109363973
27. Kendig EL, Le HH, Belcher SM. Defining hormesis: evaluation of a complex concentration response phenomenon. Int J Toxicol 2010; 29:235-46; PMID:20448256; http://dx.doi. org/10.1177/1091581810363012
28. Calabrese V, Cornelius C, Cuzzocrea S, Iavicoli I, Rizzarelli E, Calabrese EJ. Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Mol Aspects Med 2011; 32:279-304; PMID:22020114; http://dx.doi.org/10.1016/j. mam.2011.10.007
29. Martins I, Galluzzi L, Kroemer G. Hormesis, cell death and aging. Aging (Albany NY) 2011; 3:821-8; PMID:21931183
30. Calabrese EJ, Iavicoli I, Calabrese V. Hormesis: why it is important to biogerontologists. Biogerontology 2012; 13:215-35; PMID:22270337; http://dx.doi. org/10.1007/s10522-012-9374-7
31. Radak Z, Chung HY, Goto S. Exercise and hormesis: oxidative stress-related adaptation for successful aging. Biogerontology 2005; 6:71-5; PMID:15834665; http://dx.doi.org/10.1007/s10522-004-7386-7
32. Rattan SIS. Anti-ageing strategies: prevention or therapy? Showing ageing from within. EMBO Rep 2005; 6(Spec No):S25-9; PMID:15995657; http://dx.doi.org/10.1038/sj.embor.7400401
33. Rattan SI. Hormetic modulation of aging and longevity by mild heat stress. Dose Response 2005; 3:533-46; PMID:18648625; http://dx.doi.org/10.2203/ dose-response.003.04.008
34. Masoro EJ. Role of hormesis in life extension by caloric restriction. Dose Response 2007; 5:163-73; PMID:18648602; http://dx.doi.org/10.2203/ doseresponse. 06-005.Masoro
35. Mattson MP. Hormesis defined. Ageing Res Rev 2008; 7:1-7; PMID:18162444; http://dx.doi. org/10.1016/j.arr.2007.08.007
36. Yashin AI. Hormesis against aging and diseases: using properties of biological adaptation for health and survival improvement. Dose Response 2009; 8:41-7; PMID:20221287; http://dx.doi.org/10.2203/doseresponse. 09-024.Yashin
37. Calabrese V, Cornelius C, Dinkova-Kostova AT, Iavicoli I, Di Paola R, Koverech A, et al. Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity. Biochim Biophys Acta 2012; 1822:753-83; PMID:22108204; http://dx.doi. org/10.1016/j.bbadis.2011.11.002
38. Calabrese EJ. Hormesis: Toxicological foundations and role in aging research. [Epub ahead of print]. Exp Gerontol 2012; PMID:22525590
39. Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, et al. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY) 2009; 1:988-1007; PMID:20157582
40. Ristow M, Schmeisser S. Extending life span by increasing oxidative stress. Free Radic Biol Med 2011; 51:327-36; PMID:21619928; http://dx.doi. org/10.1016/j.freeradbiomed.2011.05.010
41. Weiss EP, Fontana L. Caloric restriction: powerful protection for the aging heart and vasculature. Am J Physiol Heart Circ Physiol 2011; 301:H1205-19; PMID:21841020; http://dx.doi.org/10.1152/ajpheart. 00685.2011
42. Raffaghello L, Safdie F, Bianchi G, Dorff T, Fontana L, Longo VD. Fasting and differential chemotherapy protection in patients. Cell Cycle 2010; 9:4474-6; PMID:21088487; http://dx.doi.org/10.4161/cc.9.22.13954
43. Blagosklonny MV. Rapamycin-induced glucose intolerance: hunger or starvation diabetes. Cell Cycle 2011; 10:4217-24; PMID:22157190; http://dx.doi. org/10.4161/cc.10.24.18595
44. Blagosklonny MV. Once again on rapamycininduced insulin resistance and longevity: despite of or owing to. Aging (Albany NY) 2012; 4:350-8; PMID:22683661
45. Zhang D, Liu Y, Chen D. SIRT-ain relief from ageinducing stress. Aging (Albany NY) 2011; 3:158-61; PMID:21307404
46. Khanna A, Muthusamy S, Liang R, Sarojini H, Wang E. Gain of survival signaling by down-regulation of three key miRNAs in brain of calorierestricted mice. Aging (Albany NY) 2011; 3:223-36; PMID:21415464
47. Soare A, Cangemi R, Omodei D, Holloszy JO, Fontana L. Long-term calorie restriction, but not endurance exercise, lowers core body temperature in humans. Aging (Albany NY) 2011; 3:374-9; PMID:21483032
48. Longo VD, Fontana L. Intermittent supplementation with rapamycin as a dietary restriction mimetic. Aging (Albany NY) 2011; 3:1039-40; PMID:22147496
49. Lee C, Longo VD. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene 2011; 30:3305-16; PMID:21516129; http://dx.doi.org/10.1038/onc.2011.91
50. Chung JH. Using PDE inhibitors to harness the benefits of calorie restriction: lessons from resveratrol. Aging (Albany NY) 2012; 4:144-5; PMID:22388573
51. Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci 2010; 31:89-98; PMID:20097433; http://dx.doi.org/10.1016/j. tips.2009.11.004
52. Yamaza H, Komatsu T, Wakita S, Kijogi C, Park S, Hayashi H, et al. FoxO1 is involved in the antineoplastic effect of calorie restriction. Aging Cell 2010; 9:372-82; PMID:20222901; http://dx.doi. org/10.1111/j.1474-9726.2010. 00563.x
53. Anisimov VN. Metformin for aging and cancer prevention. Aging (Albany NY) 2010; 2:760-74; PMID:21084729
54. Hursting SD, Smith SM, Lashinger LM, Harvey AE, Perkins SN. Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Carcinogenesis 2010; 31:83-9; PMID:19969554; http://dx.doi.org/10.1093/carcin/ bgp280
55. Longo VD, Fontana L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci 2010; 31:89-98; PMID:20097433; http://dx.doi.org/10.1016/j. tips.2009.11.004
56. Martín-Montalvo A, Villalba JM, Navas P, de Cabo R. NRF2, cancer and calorie restriction. Oncogene 2011; 30:505-20; PMID:21057541; http://dx.doi. org/10.1038/onc.2010.492
57. Thompson HJ, McTiernan A. Weight cycling and cancer: weighing the evidence of intermittent caloric restriction and cancer risk. Cancer Prev Res (Phila) 2011; 4:1736-42; PMID:21982873; http://dx.doi. org/10.1158/1940-6207. CAPR-11-0133
58. Erkekol FO, Celik GE, Keskin O, Güllü E, Mungan D, Misirligil Z. Fasting: an important issue in asthma management compliance. Ann Allergy Asthma Immunol 2006; 97:370-4; PMID:17042144; http://dx.doi.org/10.1016/S1081- 1206(10)60803-4
59. Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med 2012; 4:24ra27; PMID:22323820; http://dx.doi. org/10.1126/scitranslmed.3003293
60. Safdie F, Brandhorst S, Wei M, Wang W, Lee C, Hwang S, et al. Fasting enhances the response of glioma to chemo-and radiotherapy. PLoS One 2012; 7:e44603; PMID:22984531; http://dx.doi. org/10.1371/journal.pone.0044603
61. Kouda K, Iki M. Beneficial effects of mild stress (hormetic effects): dietary restriction and health. J Physiol Anthropol 2010; 29:127-32; PMID:20686325; http://dx.doi.org/10.2114/jpa2.29.127
62. Lamming DW, Wood JG, Sinclair DA. Small molecules that regulate lifespan: evidence for xenohormesis. Mol Microbiol 2004; 53:1003-9; PMID:15306006; http://dx.doi.org/10.1111/j.1365-2958.2004.04209.x
63. Howitz KT, Sinclair DA. Xenohormesis: sensing the chemical cues of other species. Cell 2008; 133:387-91; PMID:18455976; http://dx.doi.org/10.1016/j. cell.2008.04.019
64. Hooper PL, Hooper PL, Tytell M, Vígh L. Xenohormesis: health benefits from an eon of plant stress response evolution. Cell Stress Chaperones 2010; 15:761-70; PMID:20524162; http://dx.doi. org/10.1007/s12192-010-0206-x
65. Son TG, Camandola S, Mattson MP. Hormetic dietary phytochemicals. Neuromolecular Med 2008; 10:236-46; PMID:18543123; http://dx.doi. org/10.1007/s12017-008-8037-y
66. Surh YJ. Xenohormesis mechanisms underlying chemopreventive effects of some dietary phytochemicals. Ann N Y Acad Sci 2011; 1229:1-6; PMID:21793832; http://dx.doi.org/10.1111/j.1749-6632.2011.06097.x
67. Joseph JA, Shukitt-Hale B, Casadesus G. Reversing the deleterious effects of aging on neuronal communication and behavior: beneficial properties of fruit polyphenolic compounds. Am J Clin Nutr 2005; 81(Suppl):313S-6S; PMID:15640496
68. Benavente-García O, Castillo J. Update on uses and properties of citrus flavonoids: new findings in anticancer, cardiovascular, and anti-inflammatory activity. J Agric Food Chem 2008; 56:6185-205; PMID:18593176; http://dx.doi.org/10.1021/jf8006568
69. Seelinger G, Merfort I, Schempp CM. Anti-oxidant, anti-inflammatory and anti-allergic activities of luteolin. Planta Med 2008; 74:1667-77; PMID:18937165; http://dx.doi.org/10.1055/s-0028-1088314
70. Chondrogianni N, Kapeta S, Chinou I, Vassilatou K, Papassideri I, Gonos ES. Anti-ageing and rejuvenating effects of quercetin. Exp Gerontol 2010; 45:763-71; PMID:20619334; http://dx.doi.org/10.1016/j. exger.2010.07.001
71. Klappan AK, Hones S, Mylonas I, Brüning A. Proteasome inhibition by quercetin triggers macroautophagy and blocks mTOR activity. Histochem Cell Biol 2012; 137:25-36; PMID:21993664; http://dx.doi.org/10.1007/s00418-011-0869-0
72. Armour SM, Baur JA, Hsieh SN, Land-Bracha A, Thomas SM, Sinclair DA. Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging (Albany NY) 2009; 1:515-28; PMID:20157535
73. Saul N, Pietsch K, Menzel R, Steinberg CE. Quercetin-mediated longevity in Caenorhabditis elegans: is DAF-16 involved? Mech Ageing Dev 2008; 129:611-3; PMID:18692520; http://dx.doi. org/10.1016/j.mad.2008.07.001
74. Wilson MA, Shukitt-Hale B, Kalt W, Ingram DK, Joseph JA, Wolkow CA. Blueberry polyphenols increase lifespan and thermotolerance in Caenorhabditis elegans. Aging Cell 2006; 5:59-68; PMID:16441844; http://dx.doi.org/10.1111/j. 1474-9726.2006.00192.x
75. Speciale A, Chirafisi J, Saija A, Cimino F. Nutritional antioxidants and adaptive cell responses: an update. Curr Mol Med 2011; 11:770-89; PMID:21999148; http://dx.doi.org/10.2174/156652411798062395
76. Rockenfeller P, Madeo F. Ageing and eating. Biochim Biophys Acta 2010; 1803:499-506; PMID:20079384; http://dx.doi.org/10.1016/j.bbamcr.2010.01.001
77. Zaveri NT. Green tea and its polyphenolic catechins: medicinal uses in cancer and noncancer applications. Life Sci 2006; 78:2073-80; PMID:16445946; http://dx.doi.org/10.1016/j.lfs.2005.12.006
78. Rattan SI, Ali RE. Hormetic prevention of molecular damage during cellular aging of human skin fibroblasts and keratinocytes. Ann N Y Acad Sci 2007; 1100:424-30; PMID:17460207; http://dx.doi. org/10.1196/annals.1395.047
79. Mattson MP. Dietary factors, hormesis and health. Ageing Res Rev 2008; 7:43-8; PMID:17913594; http://dx.doi.org/10.1016/j.arr.2007.08.004
80. Xiang L, Nakamura Y, Lim YM, Yamasaki Y, Kurokawa-Nose Y, Maruyama W, et al. Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor. Aging (Albany NY) 2011; 3:1098-109; PMID:22156377
81. Pramanik D, Campbell NR, Das S, Gupta S, Chenna V, Bisht S, et al. A composite polymer nanoparticle overcomes multidrug resistance and ameliorates doxorubicin-associated cardiomyopathy. Oncotarget 2012; 3:640-50; PMID:22791660
82. Petrovski G, Das DK. Does autophagy take a front seat in lifespan extension? J Cell Mol Med 2010; 14:2543-51; PMID:21114762; http://dx.doi. org/10.1111/j.1582-4934.2010.01196.x
83. Chung S, Yao H, Caito S, Hwang JW, Arunachalam G, Rahman I. Regulation of SIRT1 in cellular functions: role of polyphenols. Arch Biochem Biophys 2010; 501:79-90; PMID:20450879; http://dx.doi. org/10.1016/j.abb.2010.05.003
84. Sikora E, Bielak-Zmijewska A, Mosieniak G, Piwocka K. The promise of slow down ageing may come from curcumin. Curr Pharm Des 2010; 16:884-92; PMID:20388102; http://dx.doi. org/10.2174/138161210790883507
85. Queen BL, Tollefsbol TO. Polyphenols and aging. Curr Aging Sci 2010; 3:34-42; PMID:20298168
86. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 2006; 5:493-506; PMID:16732220; http://dx.doi. org/10.1038/nrd2060
87. Liu BL, Zhang X, Zhang W, Zhen HN. New enlightenment of French Paradox: resveratrol's potential for cancer chemoprevention and anti-cancer therapy. Cancer Biol Ther 2007; 6:1833-6; PMID:18087218; http://dx.doi.org/10.4161/cbt.6. 12.5161
88. Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997; 275:218-20; PMID:8985016; http://dx.doi.org/10.1126/ science.275.5297.218
89. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003; 425:191-6; PMID:12939617; http://dx.doi.org/10.1038/nature01960
90. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006; 444:337-42; PMID:17086191; http://dx.doi. org/10.1038/nature05354
91. Pearson KJ, Baur JA, Lewis KN, Peshkin L, Price NL, Labinskyy N, et al. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab 2008; 8:157-68; PMID:18599363; http://dx.doi.org/10.1016/j.cmet.2008.06.011
92. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 2006; 127:1109-22; PMID:17112576; http://dx.doi.org/10.1016/j.cell.2006.11.013
93. Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004; 430:686-9; PMID:15254550; http://dx.doi. org/10.1038/nature02789
94. Agarwal B, Baur JA. Resveratrol and life extension. Ann N Y Acad Sci 2011; 1215:138-43; PMID:21261652; http://dx.doi.org/10.1111/j.1749-6632.2010. 05850.x
95. 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; 128:546-52; PMID:17875315; http://dx.doi.org/10.1016/j. mad.2007.07.007
96. Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 2006; 16:296-300; PMID:16461283; http://dx.doi.org/10.1016/j. cub.2005.12.038
97. Blagosklonny MV. Inhibition of S6K by resveratrol: in search of the purpose. Aging (Albany NY) 2009; 1:511-4; PMID:20157534
98. Demidenko ZN, Blagosklonny MV. At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence. Cell Cycle 2009; 8:1901-4; PMID:19471118; http://dx.doi.org/10.4161/cc.8.12.8810
99. Rascón B, Hubbard BP, Sinclair DA, Amdam GV. The lifespan extension effects of resveratrol are conserved in the honey bee and may be driven by a mechanism related to caloric restriction. Aging (Albany NY) 2012; 4:499-508; PMID:22868943
100. Timmers S, Auwerx J, Schrauwen P. The journey of resveratrol from yeast to human. Aging (Albany NY) 2012; 4:146-58; PMID:22436213
101. Morselli E, Galluzzi L, Kepp O, Criollo A, Maiuri MC, Tavernarakis N, et al. Autophagy mediates pharmacological lifespan extension by spermidine and resveratrol. Aging (Albany NY) 2009; 1:961-70; PMID:20157579
102. Hofseth LJ, Singh UP, Singh NP, Nagarkatti M, Nagarkatti PS. Taming the beast within: resveratrol suppresses colitis and prevents colon cancer. Aging (Albany NY) 2010; 2:183-4; PMID:20436227
103. Vetterli L, Maechler P. Resveratrol-activated SIRT1 in liver and pancreatic β-cells: a Janus head looking to the same direction of metabolic homeostasis. Aging (Albany NY) 2011; 3:444-9; PMID:21483037
104. Antosh M, Fox D, Helfand SL, Cooper LN, Neretti N. New comparative genomics approach reveals a conserved health span signature across species. Aging (Albany NY) 2011; 3:576-83; PMID:21775776
105. Chung JH. Using PDE inhibitors to harness the benefits of calorie restriction: lessons from resveratrol. Aging (Albany NY) 2012; 4:144-5; PMID:22388573
106. Vang O, Ahmad N, Baile CA, Baur JA, Brown K, Csiszar A, et al. What is new for an old molecule? Systematic review and recommendations on the use of resveratrol. PLoS One 2011; 6:e19881; PMID:21698226; http://dx.doi.org/10.1371/ journal. pone.0019881
107. Hardie DG. Sensing of energy and nutrients by AMP-activated protein kinase. Am J Clin Nutr 2011; 93:891S-6; PMID:21325438; http://dx.doi. org/10.3945/ajcn.110.001925
108. Do GM, Jung UJ, Park HJ, Kwon EY, Jeon SM, McGregor RA, et al. Resveratrol ameliorates diabetes-related metabolic changes via activation of AMP activated protein kinase and its downstream targets in db/db mice. Mol Nutr Food Res 2012; 56:1282-91; PMID:22715031; http://dx.doi.org/10.1002/mnfr. 201200067
109. Chen S, Xiao X, Feng X, Li W, Zhou N, Zheng L, et al. Resveratrol induces Sirt1-dependent apoptosis in 3T3-L1 preadipocytes by activating AMPK and suppressing AKT activity and survivin expression. J Nutr Biochem 2012; 23:1100-12; PMID:22137261; http://dx.doi.org/10.1016/j.jnutbio.2011.06.003
110. Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens GH, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011; 14:612-22; PMID:22055504; http://dx.doi.org/10.1016/j. cmet.2011.10.002
111. Hsu CL, Yen GC. Phenolic compounds: evidence for inhibitory effects against obesity and their underlying molecular signaling mechanisms. Mol Nutr Food Res 2008; 52:53-61; PMID:18081207; http://dx.doi. org/10.1002/mnfr. 200700393
112. Crozier A, Jaganath IB, Clifford MN. Dietary phenolics: chemistry, bioavailability and effects on health. Nat Prod Rep 2009; 26:1001-43; PMID:19636448; http://dx.doi.org/10.1039/b802662a
113. Cicerale S, Conlan XA, Sinclair AJ, Keast RS. Chemistry and health of olive oil phenolics. Crit Rev Food Sci Nutr 2009; 49:218-36; PMID:19093267; http://dx.doi.org/10.1080/10408390701856223
114. Colomer R, Menéndez JA. Mediterranean diet, olive oil and cancer. Clin Transl Oncol 2006; 8:15-21; PMID:16632435; http://dx.doi.org/10.1007/ s12094-006-0090-0
115. Menendez JA, Lupu R. Mediterranean dietary traditions for the molecular treatment of human cancer: anti-oncogenic actions of the main olive oil's monounsaturated fatty acid oleic acid (18:1n-9). Curr Pharm Biotechnol 2006; 7:495-502; PMID:17168666; http://dx.doi.org/10.2174/138920106779116900
116. Escrich E, Moral R, Grau L, Costa I, Solanas M. Molecular mechanisms of the effects of olive oil and other dietary lipids on cancer. Mol Nutr Food Res 2007; 51:1279-92; PMID:17879998
117. Colomer R, Lupu R, Papadimitropoulou A, Vellón L, Vázquez-Martín A, Brunet J, et al. Giacomo Castelvetro's salads. Anti-HER2 oncogene nutraceuticals since the 17th century? Clin Transl Oncol 2008; 10:30-4; PMID:18208790; http://dx.doi. org/10.1007/s12094-008-0151-7
118. López-Miranda J, Pérez-Jiménez F, Ros E, De Caterina R, Badimón L, Covas MI, et al. Olive oil and health: summary of the II international conference on olive oil and health consensus report, Jaén and Córdoba (Spain) 2008. Nutr Metab Cardiovasc Dis 2010; 20:284-94; PMID:20303720; http://dx.doi.org/10.1016/j.numecd.2009.12.007
119. Escrich E, Solanas M, Moral R, Costa I, Grau L. Are the olive oil and other dietary lipids related to cancer? Experimental evidence. Clin Transl Oncol 2006; 8:868-83; PMID:17169760; http://dx.doi. org/10.1007/s12094-006-0150-5
120. Galli C, Visioli F. Antioxidant and other activities of phenolics in olives/olive oil, typical components of the Mediterranean diet. Lipids 1999; 34:23-6; PMID:10188593; http://dx.doi.org/10.1007/BF02562224
121. Owen RW, Giacosa A, Hull WE, Haubner R, Spiegelhalder B, Bartsch H. The antioxidant/anticancer potential of phenolic compounds isolated from olive oil. Eur J Cancer 2000; 36:1235-47; PMID:10882862; http://dx.doi.org/10.1016/S0959- 8049(00)00103-9
122. Owen RW, Mier W, Giacosa A, Hull WE, Spiegelhalder B, Bartsch H. Identification of lignans as major components in the phenolic fraction of olive oil. Clin Chem 2000; 46:976-88; PMID:10894841
123. Visioli F, Galli C. Phenolics from olive oil and its waste products. Biological activities in in vitro and in vivo studies. World Rev Nutr Diet 2001; 88:233-7; PMID:11935962; http://dx.doi. org/10.1159/000059757
124. Visioli F, Poli A, Gall C. Antioxidant and other biological activities of phenols from olives and olive oil. Med Res Rev 2002; 22:65-75; PMID:11746176; http://dx.doi.org/10.1002/med.1028
125. Visioli F, Galli C. Biological properties of olive oil phytochemicals. Crit Rev Food Sci Nutr 2002; 42:209-21; PMID:12058980; http://dx.doi. org/10.1080/10408690290825529
126. Beauchamp GK, Keast RS, Morel D, Lin J, Pika J, Han Q, et al. Phytochemistry: ibuprofen-like activity in extra-virgin olive oil. Nature 2005; 437:45-6; PMID:16136122; http://dx.doi. org/10.1038/437045a
127. Carrasco-Pancorbo A, Cerretani L, Bendini A, Segura-Carretero A, Gallina-Toschi T, Fernandez-Gutiérrez A. Analytical determination of polyphenols in olive oils. J Sep Sci 2005; 28:837-58; PMID:16013811; http://dx.doi.org/10.1002/jssc.200500032
128. Bendini A, Cerretani L, Carrasco-Pancorbo A, Gómez-Caravaca AM, Segura-Carretero A, Fernández-Gutiérrez A, et al. Phenolic molecules in virgin olive oils: a survey of their sensory properties, health effects, antioxidant activity and analytical methods. An overview of the last decade. Molecules 2007; 12:1679-719; PMID:17960082; http://dx.doi. org/10.3390/12081679
129. García-Villalba R, Carrasco-Pancorbo A, Oliveras-Ferraros C, Vázquez-Martín A, Menéndez JA, Segura-Carretero A, et al. Characterization and quantification of phenolic compounds of extra-virgin olive oils with anticancer properties by a rapid and resolutive LC-ESI-TOF MS method. J Pharm Biomed Anal 2010; 51:416-29; PMID:19596535; http://dx.doi.org/10.1016/j. jpba.2009.06.021
130. García-Villalba R, Carrasco-Pancorbo A, Vázquez- Martín A, Oliveras-Ferraros C, Menéndez JA, Segura-Carretero A, et al. A 2-D-HPLC-CE platform coupled to ESI-TOF-MS to characterize the phenolic fraction in olive oil. Electrophoresis 2009; 30:2688-701; PMID:19650044; http://dx.doi.org/10.1002/elps.200800807
131. Owen RW, Giacosa A, Hull WE, Haubner R, Würtele G, Spiegelhalder B, et al. Olive-oil consumption and health: the possible role of antioxidants. Lancet Oncol 2000; 1:107-12; PMID:11905662; http://dx.doi.org/10.1016/S1470- 2045(00)00015-2
132. Servili M, Esposto S, Fabiani R, Urbani S, Taticchi A, Mariucci F, et al. Phenolic compounds in olive oil: antioxidant, health and organoleptic activities according to their chemical structure. Inflammopharmacology 2009; 17:76-84; PMID:19234678; http://dx.doi. org/10.1007/s10787-008-8014-y
133. Raederstorff D. Antioxidant activity of olive polyphenols in humans: a review. Int J Vitam Nutr Res 2009; 79:152-65; PMID:20209466; http://dx.doi. org/10.1024/0300-9831.79.3.152
134. Sinclair DA. Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev 2005; 126:987-1002; PMID:15893363; http://dx.doi.org/10.1016/j.mad.2005.03.019
135. Way TD, Kao MC, Lin JK. Apigenin induces apoptosis through proteasomal degradation of HER2/neu in HER2/neu-overexpressing breast cancer cells via the phosphatidylinositol 3-kinase/Aktdependent pathway. J Biol Chem 2004; 279:4479-89; PMID:14602723; http://dx.doi.org/10.1074/jbc. M305529200
136. Way TD, Kao MC, Lin JK. Degradation of HER2/neu by apigenin induces apoptosis through cytochrome c release and caspase-3 activation in HER2/neu-overexpressing breast cancer cells. FEBS Lett 2005; 579:145-52; PMID:15620704; http://dx.doi. org/10.1016/j.febslet.2004.11.061
137. Shimizu M, Deguchi A, Joe AK, Mckoy JF, Moriwaki H, Weinstein IB. EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells. J Exp Ther Oncol 2005; 5:69-78; PMID:16416603
138. Shimizu M, Deguchi A, Hara Y, Moriwaki H, Weinstein IB. EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells. Biochem Biophys Res Commun 2005; 334:947-53; PMID:16053920; http://dx.doi. org/10.1016/j.bbrc.2005.06.182
139. Shimizu M, Deguchi A, Lim JT, Moriwaki H, Kopelovich L, Weinstein IB. (-)-Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells. Clin Cancer Res 2005; 11:2735-46; PMID:15814656; http://dx.doi.org/10.1158/1078-0432.CCR-04-2014
140. Chiang CT, Way TD, Lin JK. Sensitizing HER2-overexpressing cancer cells to luteolin-induced apoptosis through suppressing p21(WAF1/CIP1) expression with rapamycin. Mol Cancer Ther 2007; 6:2127-38; PMID:17620442; http://dx.doi. org/10.1158/1535-7163.MCT-07-0107
141. Menendez JA, Vazquez-Martin A, Colomer R, Brunet J, Carrasco-Pancorbo A, Garcia-Villalba R, et al. Olive oil's bitter principle reverses acquired autoresistance to trastuzumab (Herceptin) in HER2-overexpressing breast cancer cells. BMC Cancer 2007; 7:80; PMID:17490486; http://dx.doi. org/10.1186/1471- 2407-7-8
142. Menendez JA, Vazquez-Martin A, Oliveras-Ferraros C, Garcia-Villalba R, Carrasco-Pancorbo A, Fernandez-Gutierrez A, et al. Analyzing effects of extra-virgin olive oil polyphenols on breast cancerassociated fatty acid synthase protein expression using reverse-phase protein microarrays. Int J Mol Med 2008; 22:433-9; PMID:18813848
143. Menendez JA, Vazquez-Martin A, Oliveras-Ferraros C, Garcia-Villalba R, Carrasco-Pancorbo A, Fernandez-Gutierrez A, et al. Extra-virgin olive oil polyphenols inhibit HER2 (erbB-2)-induced malignant transformation in human breast epithelial cells: relationship between the chemical structures of extra-virgin olive oil secoiridoids and lignans and their inhibitory activities on the tyrosine kinase activity of HER2. Int J Oncol 2009; 34:43-51; PMID:19082476
144. Menendez JA, Vazquez-Martin A, Garcia-Villalba R, Carrasco-Pancorbo A, Oliveras-Ferraros C, Fernandez-Gutierrez A, et al. tab Anti-HER2 (erbB-2) oncogene effects of phenolic compounds directly isolated from commercial Extra-Virgin Olive Oil (EVOO). BMC Cancer 2008; 8:377; PMID:19094209; http://dx.doi.org/10.1186/1471-2407-8-377
145. Lozano-Sánchez J, Segura-Carretero A, Menendez JA, Oliveras-Ferraros C, Cerretani L, Fernández-Gutiérrez A. Prediction of extra virgin olive oil varieties through their phenolic profile. Potential cytotoxic activity against human breast cancer cells. J Agric Food Chem 2010; 58:9942-55; PMID:20795736; http://dx.doi.org/10.1021/jf101502q
146. 2/M arrest and hyperacetylation of Histone H3. Int J Oncol 2011; 38:1533-47; PMID:21455577
147. Vazquez-Martin A, Fernández-Arroyo S, Cufí S, Oliveras-Ferraros C, Lozano-Sánchez J, Vellón L, et al. Phenolic secoiridoids in extra virgin olive oil impede fibrogenic and oncogenic epithelial-to-mesenchymal transition: extra virgin olive oil as a source of novel antiaging phytochemicals. Rejuvenation Res 2012; 15:3-21; PMID:22229524; http://dx.doi. org/10.1089/rej.2011.1203
148. García-Villalba R, Carrasco-Pancorbo A, Oliveras-Ferraros C, Menéndez JA, Segura-Carretero A, Fernández-Gutiérrez A. Uptake and metabolism of olive oil polyphenols in human breast cancer cells using nano-liquid chromatography coupled to electrospray ionization-time of flight-mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2012; 898:69-77; PMID:22608806; http://dx.doi. org/10.1016/j.jchromb.2012.04.021
149. Roldán C, de la Torre A, Mota S, Morales-Soto A, Menéndez J, Segura-Carretero A. Identification of active compounds in vegetal extracts based on correlation between activity and HPLC-MS data. Food Chem 2013; 136:392-9; PMID:23122076; http://dx.doi.org/10.1016/j.foodchem.2012.08.027
150. Buckland G, Agudo A, Travier N, Huerta JM, Cirera L, Tormo MJ, et al. Adherence to the Mediterranean diet reduces mortality in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). Br J Nutr 2011; 106:1581-91; PMID:21736834; http://dx.doi.org/10.1017/ S0007114511002078
151. Lagiou P, Trichopoulos D, Sandin S, Lagiou A, Mucci L, Wolk A, et al. Mediterranean dietary pattern and mortality among young women: a cohort study in Sweden. Br J Nutr 2006; 96:384-92; PMID:16923235; http://dx.doi.org/10.1079/ BJN20061824
152. Trichopoulou A, Orfanos P, Norat T, Bueno-de-Mesquita B, Ocké MC, Peeters PH, et al. Modified Mediterranean diet and survival: EPIC-elderly prospective cohort study. BMJ 2005; 330:991; PMID:15820966; http://dx.doi.org/ 10.1136/bmj.38415.644155.8F
153. Trichopoulou A, Dilis V. Olive oil and longevity. Mol Nutr Food Res 2007; 51:1275-8; PMID:17879997
154. Trichopoulou A. Traditional Mediterranean diet and longevity in the elderly: a review. Public Health Nutr 2004; 7:943-7; PMID:15482622; http://dx.doi. org/10.1079/PHN2004558
155. Trichopoulou A, Critselis E. Mediterranean diet and longevity. Eur J Cancer Prev 2004; 13:453-6; PMID:15452459; http://dx.doi. org/10.1097/00008469- 200410000-00014
156. Trichopoulou A, Costacou T, Bamia C, Trichopoulos D. Adherence to a Mediterranean diet and survival in a Greek population. N Engl J Med 2003; 348:2599-608; PMID:12826634; http://dx.doi.org/10.1056/NEJMoa025039
157. Frankel EN. Nutritional and biological properties of extra virgin olive oil. J Agric Food Chem 2011; 59:785-92; PMID:21210703; http://dx.doi. org/10.1021/jf103813t
158. Blagosklonny MV. Aging: ROS or TOR. Cell Cycle 2008; 7:3344-54; PMID:18971624; http://dx.doi. org/10.4161/cc.7.21.6965
159. Hunt PR, Son TG, Wilson MA, Yu QS, Wood WH, Zhang Y, et al. Extension of lifespan in C. elegans by naphthoquinones that act through stress hormesis mechanisms. PLoS One 2011; 6:e21922; PMID:21765926; http://dx.doi.org/10.1371/ journal. pone.0021922
160. Hwang AB, Lee SJ. Regulation of life span by mitochondrial respiration: the HIF-1 and ROS connection. Aging (Albany NY) 2011; 3:304-10; PMID:21389351
161. Keaney M, Matthijssens F, Sharpe M, Vanfleteren J, Gems D. Superoxide dismutase mimetics elevate superoxide dismutase activity in vivo but do not retard aging in the nematode Caenorhabditis elegans. Free Radic Biol Med 2004; 37:239-50; PMID:15203195; http://dx.doi.org/10.1016/j.freeradbiomed. 2004.04.005
162. Doonan R, McElwee JJ, Matthijssens F, Walker GA, Houthoofd K, Back P, et al. Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev 2008; 22:3236-41; PMID:19056880; http://dx.doi. org/10.1101/gad.504808
163. Van Raamsdonk JM, Hekimi S. Deletion of the mitochondrial superoxide dismutase sod-2 extends lifespan in Caenorhabditis elegans. PLoS Genet 2009; 5:e1000361; PMID:19197346; http://dx.doi. org/10.1371/journal.pgen.1000361
164. Gems D, Doonan R. Antioxidant defense and aging in C. elegans: is the oxidative damage theory of aging wrong? Cell Cycle 2009; 8:1681-7; PMID:19411855; http://dx.doi.org/10.4161/cc.8.11.8595
165. Lapointe J, Hekimi S. When a theory of aging ages badly. Cell Mol Life Sci 2010; 67:1-8; PMID:19730800; http://dx.doi.org/10.1007/s00018-009-0138-8
166. Edman U, Garcia AM, Busuttil RA, Sorensen D, Lundell M, Kapahi P, et al. Lifespan extension by dietary restriction is not linked to protection against somatic DNA damage in Drosophila melanogaster. Aging Cell 2009; 8:331-8; PMID:19627272; http://dx.doi.org/10.1111/j.1474-9726.2009.00480.x
167. Van Raamsdonk JM, Meng Y, Camp D, Yang W, Jia X, Bénard C, et al. Decreased energy metabolism extends life span in Caenorhabditis elegans without reducing oxidative damage. Genetics 2010; 185:559-71; PMID:20382831; http://dx.doi.org/10.1534/genetics.110.115378
168. Van Raamsdonk JM, Hekimi S. Reactive Oxygen Species and Aging in Caenorhabditis elegans: Causal or Casual Relationship? Antioxid Redox Signal 2010; 13:1911-53; PMID:20568954; http://dx.doi. org/10.1089/ars.2010.3215
169. Yang W, Li J, Hekimi S. A Measurable increase in oxidative damage due to reduction in superoxide detoxification fails to shorten the life span of long-lived mitochondrial mutants of Caenorhabditis elegans. Genetics 2007; 177:2063-74; PMID:18073424; http://dx.doi.org/10.1534/genetics.107.080788
170. Guachalla LM, Rudolph KL. ROS induced DNA damage and checkpoint responses: influences on aging? Cell Cycle 2010; 9:4058-60; PMID:20935491; http://dx.doi.org/10.4161/cc.9.20.13577
171. Yang W, Hekimi S. A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol 2010; 8:e1000556; PMID:21151885; http://dx.doi.org/10.1371/journal.pbio.1000556
172. Hekimi S, Lapointe J, Wen Y. Taking a "good" look at free radicals in the aging process. Trends Cell Biol 2011; 21:569-76; PMID:21824781; http://dx.doi. org/10.1016/j.tcb.2011.06.008
173. Sanz A, Fernández-Ayala DJ, Stefanatos RK, Jacobs HT. Mitochondrial ROS production correlates with, but does not directly regulate lifespan in Drosophila. Aging (Albany NY) 2010; 2:200-23; PMID:20453260
174. Pani G. P66SHC and ageing: ROS and TOR? Aging (Albany NY) 2010; 2:514-8; PMID:20689155
175. Cabreiro F, Ackerman D, Doonan R, Araiz C, Back P, Papp D, et al. Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage. Free Radic Biol Med 2011; 51:1575-82; PMID:21839827; http://dx.doi.org/10.1016/j. freeradbiomed.2011.07.020
176. Speakman JR, Selman C. The free-radical damage theory: Accumulating evidence against a simple link of oxidative stress to ageing and lifespan. Bioessays 2011; 33:255-9; PMID:21290398; http://dx.doi. org/10.1002/bies. 201000132
177. Lee SJ, Hwang AB, Kenyon C. Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr Biol 2010; 20:2131-6; PMID:21093262; http://dx.doi. org/10.1016/j.cub.2010.10.057
178. Rodriguez KA, Wywial E, Perez VI, Lambert AJ, Edrey YH, Lewis KN, et al. Walking the oxidative stress tightrope: a perspective from the naked mole-rat, the longest-living rodent. Curr Pharm Des 2011; 17:2290-307; PMID:21736541; http://dx.doi. org/10.2174/138161211797052457
179. Cañuelo A, Gilbert-López B, Pacheco-Liñán P, Martínez-Lara E, Siles E, Miranda-Vizuete A. Tyrosol, a main phenol present in extra virgin olive oil, increases lifespan and stress resistance in Caenorhabditis elegans. Mech Ageing Dev 2012; 133:563-74; PMID:22824366; http://dx.doi. org/10.1016/j.mad.2012.07.004
180. Blagosklonny MV. Hormesis does not make sense except in the light of TOR-driven aging. Aging (Albany NY) 2011; 3:1051-62; PMID:22166724
181. Mayer MP, Bukau B. Hsp70 chaperones: cellular functions and molecular mechanism. Cell Mol Life Sci 2005; 62:670-84; PMID:15770419; http://dx.doi.org/10.1007/s00018-004-4464-6
182. Brocchieri L, Conway de Macario E, Macario AJ. hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evol Biol 2008; 8:19; PMID:18215318; http://dx.doi. org/10.1186/1471-2148-8-19
183. Daugaard M, Rohde M, Jäättelä M. The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions. FEBS Lett 2007; 581:3702-10; PMID:17544402; http://dx.doi. org/10.1016/j. febslet.2007.05.039
184. Neznanov N, Komarov AP, Neznanova L, Stanhope-Baker P, Gudkov AV. Proteotoxic stress targeted therapy (PSTT): induction of protein misfolding enhances the antitumor effect of the proteasome inhibitor bortezomib. Oncotarget 2011; 2:209-21; PMID:21444945
185. Leung TKC, Rajendran MY, Monfries C, Hall C, Lim L. The human heat-shock protein family. Expression of a novel heat-inducible HSP70 (HSP70B') and isolation of its cDNA and genomic DNA. Biochem J 1990; 267:125-32; PMID:2327978
186. Leung TKC, Hall C, Rajendran M, Spurr NK, Lim L. The human heat-shock genes HSPA6 and HSPA7 are both expressed and localize to chromosome 1. Genomics 1992; 12:74-9; PMID:1346391; http://dx.doi.org/10.1016/0888-7543(92)90409-L
187. Noonan EJ, Place RF, Giardina C, Hightower LE. Hsp70B' regulation and function. Cell Stress Chaperones 2007; 12:219-29; PMID:17915554; http://dx.doi.org/10.1379/CSC-278.1
188. Rohde M, Daugaard M, Jensen MH, Helin K, Nylandsted J, Jäättelä M. Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms. Genes Dev 2005; 19:570-82; PMID:15741319; http://dx.doi.org/10.1101/gad.305405
189. Milner CM, Campbell RD. Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics 1990; 32:242-51; PMID:1700760; http://dx.doi.org/10. 1007/BF00187095
190. Sargent CA, Dunham I, Trowsdale J, Campbell RD. Human major histocompatibility complex contains genes for the major heat shock protein HSP70. Proc Natl Acad Sci U S A 1989; 86:1968-72; PMID:2538825; http://dx.doi.org/10.1073/pnas.86.6.1968
191. Son WY, Hwang SH, Han CT, Lee JH, Kim S, Kim YC. Specific expression of heat shock protein HspA2 in human male germ cells. Mol Hum Reprod 1999; 5:1122-6; PMID:10587366; http://dx.doi. org/10.1093/molehr/5.12.1122
192. Govin J, Caron C, Escoffier E, Ferro M, Kuhn L, Rousseaux S, et al. Post-meiotic shifts in HSPA2/HSP70.2 chaperone activity during mouse spermatogenesis. J Biol Chem 2006; 281:37888-92; PMID:17035236; http://dx.doi.org/10.1074/jbc. M608147200
193. Zhu D, Dix DJ, Eddy EM. HSP70-2 is required for CDC2 kinase activity in meiosis I of mouse spermatocytes. Development 1997; 124:3007-14; PMID:9247342
194. Feng HL, Sandlow JI, Sparks AET. Decreased expression of the heat shock protein hsp70-2 is associated with the pathogenesis of male infertility. Fertil Steril 2001; 76:1136-9; PMID:11730740; http://dx.doi. org/10.1016/S0015-0282(01) 02892-8
195. Svärd M, Biterova EI, Bourhis JM, Guy JE. The crystal structure of the human co-chaperone P58(IPK). PLoS One 2011; 6:e22337; PMID:21799829; http://dx.doi.org/10.1371/journal.pone.0022337
196. Yan W, Frank CL, Korth MJ, Sopher BL, Novoa I, Ron D, et al. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc Natl Acad Sci U S A 2002; 99:15920-5; PMID:12446838; http://dx.doi.org/10.1073/pnas.252341799
197. Wiseman RL, Haynes CM, Ron D. Snap Shot: The unfolded protein response. Cell 2010; 140:590-590, e2; PMID:20178750; http://dx.doi.org/10.1016/j. cell.2010.02.006
198. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007; 8:519-29; PMID:17565364; http://dx.doi.org/10.1038/nrm2199
199. Zhang K, Kaufman RJ. The unfolded protein response: a stress signaling pathway critical for health and disease. Neurology 2006; 66(Suppl 1):S102-9; PMID:16432136; http://dx.doi.org/10.1212/01. wnl.0000192306.98198.ec
200. Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell 2010; 40:280-93; PMID:20965422; http://dx.doi.org/10.1016/j. molcel.2010.09.023
201. Endo S, Hiramatsu N, Hayakawa K, Okamura M, Kasai A, Tagawa Y, et al. Geranylgeranylacetone, an inducer of the 70-kDa heat shock protein (HSP70), elicits unfolded protein response and coordinates cellular fate independently of HSP70. Mol Pharmacol 2007; 72:1337-48; PMID:17702888; http://dx.doi. org/10.1124/mol.107.039164
202. Haynes CM, Ron D. The mitochondrial UPR-protecting organelle protein homeostasis. J Cell Sci 2010; 123:3849-55; PMID:21048161; http://dx.doi. org/10.1242/jcs.075119
203. Lin JH, Li H, Yasumura D, Cohen HR, Zhang C, Panning B, et al. IRE1 signaling affects cell fate during the unfolded protein response. Science 2007; 318:944-9; PMID:17991856; http://dx.doi. org/10.1126/science.1146361
204. Debnath J, Baehrecke EH, Kroemer G. Does autophagy contribute to cell death? Autophagy 2005; 1:66-74; PMID:16874022; http://dx.doi.org/10.4161/auto.1. 2.1738
205. Liu BQ, Gao YY, Niu XF, Xie JS, Meng X, Guan Y, et al. Implication of unfolded protein response in resveratrol-induced inhibition of K562 cell proliferation. Biochem Biophys Res Commun 2010; 391:778-82; PMID:19944671; http://dx.doi.org/10.1016/j. bbrc.2009.11.137
206. Yan Y, Gao YY, Liu BQ, Niu XF, Zhuang Y, Wang HQ. Resveratrol-induced cytotoxicity in human Burkitt's lymphoma cells is coupled to the unfolded protein response. BMC Cancer 2010; 10:445; PMID:20723265; http://dx.doi.org/10. 1186/1471-2407-10-445
207. Woo KJ, Lee TJ, Lee SH, Lee JM, Seo JH, Jeong YJ, et al. Elevated gadd153/chop expression during resveratrol-induced apoptosis in human colon cancer cells. Biochem Pharmacol 2007; 73:68-76; PMID:17049495; http://dx.doi.org/10.1016/j. bcp.2006.09.015
208. Viswanathan M, Kim SK, Berdichevsky A, Guarente L. A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life span. Dev Cell 2005; 9:605-15; PMID:16256736; http://dx.doi. org/10.1016/j.devcel.2005.09. 017
209. Chinta SJ, Poksay KS, Kaundinya G, Hart M, Bredesen DE, Andersen JK, et al. Endoplasmic reticulum stress-induced cell death in dopaminergic cells: effect of resveratrol. J Mol Neurosci 2009; 39:157-68; PMID:19145491; http://dx.doi.org/10.1007/s12031-008-9170-7
210. Hwang JT, Kwak DW, Lin SK, Kim HM, Kim YM, Park OJ. Resveratrol induces apoptosis in chemoresistant cancer cells via modulation of AMPK signaling pathway. Ann N Y Acad Sci 2007; 1095:441-8; PMID:17404056; http://dx.doi.org/10. 1196/annals.1397.047
211. Heiss EH, Schilder YD, Dirsch VM. Chronic treatment with resveratrol induces redox stress-and ataxia telangiectasia-mutated (ATM)-dependent senescence in p53-positive cancer cells. J Biol Chem 2007; 282:26759-66; PMID:17626009; http://dx.doi. org/10.1074/jbc.M703229200
212. Low IC, Chen ZX, Pervaiz S. Bcl-2 modulates resveratrol-induced ROS production by regulating mitochondrial respiration in tumor cells. Antioxid Redox Signal 2010; 13:807-19; PMID:20367277; http://dx.doi.org/10.1089/ars.2009. 3050
213. Hussain AR, Uddin S, Bu R, Khan OS, Ahmed SO, Ahmed M, et al. Resveratrol suppresses constitutive activation of AKT via generation of ROS and induces apoptosis in diffuse large B cell lymphoma cell lines. PLoS One 2011; 6:e24703; PMID:21931821; http://dx.doi.org/10.1371/journal.pone.0024703
214. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a doubleedged sword? Antioxid Redox Signal 2007; 9:2277-93; PMID:17979528; http://dx.doi.org/10.1089/ars.2007.1782
215. Khanal P, Oh WK, Yun HJ, Namgoong GM, Ahn SG, Kwon SM, et al. p-HPEA-EDA, a phenolic compound of virgin olive oil, activates AMP activated protein kinase to inhibit carcinogenesis. Carcinogenesis 2011; 32:545-53; PMID:21216846; http://dx.doi.org/10.1093/carcin/bgr001
216. Hao J, Shen W, Yu G, Jia H, Li X, Feng Z, et al. Hydroxytyrosol promotes mitochondrial biogenesis and mitochondrial function in 3T3-L1 adipocytes. J Nutr Biochem 2010; 21:634-44; PMID:19576748; http://dx.doi.org/10.1016/j.jnutbio. 2009.03.012
217. Smith JJ, Kenney RD, Gagne DJ, Frushour BP, Ladd W, Galonek HL, et al. Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. BMC Syst Biol 2009; 3:31; PMID:19284563; http://dx.doi.org/10.1186/1752-0509-3-31
218. Wolter F, Turchanowa L, Stein J. Resveratrolinduced modification of polyamine metabolism is accompanied by induction of c-Fos. Carcinogenesis 2003; 24:469-74; PMID:12663506; http://dx.doi. org/10.1093/carcin/24.3.469
219. Athar M, Back JH, Kopelovich L, Bickers DR, Kim AL. Multiple molecular targets of resveratrol: Anticarcinogenic mechanisms. Arch Biochem Biophys 2009; 486:95-102; PMID:19514131; http://dx.doi. org/10.1016/j.abb.2009.01.018
220. Chen A, Davis BH, Bissonnette M, Scaglione-Sewell B, Brasitus TA. 1,25-Dihydroxyvitamin D(3) stimulates activator protein-1-dependent Caco-2 cell differentiation. J Biol Chem 1999; 274:35505-13; PMID:10585423; http://dx.doi.org/10.1074/jbc.274.50.35505
221. Souleimani A, Asselin C. Regulation of C-fos expression by sodium butyrate in the human colon carcinoma cell line Caco-2. Biochem Biophys Res Commun 1993; 193:330-6; PMID:8503924; http://dx.doi. org/10.1006/bbrc.1993.1628
222. Minois N, Carmona-Gutierrez D, Madeo F. Polyamines in aging and disease. Aging (Albany NY) 2011; 3:716-32; PMID:21869457
223. Eisenberg T, Knauer H, Schauer A, Büttner S, Ruckenstuhl C, Carmona-Gutierrez D, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol 2009; 11:1305-14; PMID:19801973; http://dx.doi.org/10. 1038/ncb1975
224. Madeo F, Eisenberg T, Büttner S, Ruckenstuhl C, Kroemer G. Spermidine: a novel autophagy inducer and longevity elixir. Autophagy 2010; 6:160-2; PMID:20110777; http://dx.doi.org/10.4161/auto.6.1.10600
225. Madeo F, Tavernarakis N, Kroemer G. Can autophagy promote longevity? Nat Cell Biol 2010; 12:842-6; PMID:20811357; http://dx.doi.org/10.1038/ncb0910-842
226. Morselli E, Mariño G, Bennetzen MV, Eisenberg T, Megalou E, Schroeder S, et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J Cell Biol 2011; 192:615-29; PMID:21339330; http://dx.doi. org/10.1083/jcb.201008167
227. Mariño G, Morselli E, Bennetzen MV, Eisenberg T, Megalou E, Schroeder S, et al. Longevity-relevant regulation of autophagy at the level of the acetylproteome. Autophagy 2011; 7:647-9; PMID:21460620; http://dx.doi.org/ 10.4161/auto.7.6.15191
228. Rubinsztein DC, Mariño G, Kroemer G. Autophagy and aging. Cell 2011; 146:682-95; PMID:21884931; http://dx.doi.org/10.1016/j.cell.2011.07.030
229. Bennetzen MV, Mariño G, Pultz D, Morselli E, Færgeman NJ, Kroemer G, et al. Phosphoproteomic analysis of cells treated with longevity-related autophagy inducers. Cell Cycle 2012; 11:1827-40; PMID:22517431; http://dx.doi.org/10.4161/cc.20233
230. Minois N, Carmona-Gutierrez D, Bauer MA, Rockenfeller P, Eisenberg T, Brandhorst S, et al. Spermidine promotes stress resistance in Drosophila melanogaster through autophagy-dependent and-independent pathways. Cell Death Dis 2012; 3:e401; PMID:23059820; http://dx.doi.org/10.1038/cddis.2012.139
231. Bauer MA, Carmona-Gutiérrez D, Ruckenstuhl C, Reisenbichler A, Megalou EV, Eisenberg T, et al. Spermidine promotes mating and fertilization efficiency in model organisms. [Epub ahead of print]. Cell Cycle 2012; 12; PMID:23255134
232. Liu T, Liu PY, Marshall GM. The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res 2009; 69:1702-5; PMID:19244112; http://dx.doi.org/10.1158/0008-5472.CAN-08-3365
233. 2 cells. Am J Physiol Cell Physiol 2012; 303:C4-13; PMID:22378745; http://dx.doi. org/10.1152/ajpcell.00296.2011
234. Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell 2008; 14:312-23; PMID:18835033; http://dx.doi.org/10.1016/j.ccr. 2008.09.001
235. Fu M, Liu M, Sauve AA, Jiao X, Zhang X, Wu X, et al. Hormonal control of androgen receptor function through SIRT1. Mol Cell Biol 2006; 26:8122-35; PMID:16923962; http://dx.doi.org/10.1128/MCB.00289-06
236. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschöp MH. Sirt1 protects against high-fat dietinduced metabolic damage. Proc Natl Acad Sci U S A 2008; 105:9793-8; PMID:18599449; http://dx.doi. org/10.1073/pnas.0802917105
237. Herranz D, Serrano M. Impact of Sirt1 on mammalian aging. Aging (Albany NY) 2010; 2:315-6; PMID:20562473
238. Herranz D, Muñoz-Martin M, Cañamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 2010; 1:3; PMID:20975665; http://dx.doi.org/10.1038/ncomms1001
239. Herranz D, Serrano M. SIRT1: recent lessons from mouse models. Nat Rev Cancer 2010; 10:819-23; PMID:21102633; http://dx.doi.org/10.1038/nrc2962
240. Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 2004; 51:1-28; PMID:15207251; http://dx.doi.org/10.1016/j. critrevonc. 2004.04.007
241. Menendez JA, Vellon L, Oliveras-Ferraros C, Cufí S, Vazquez-Martin A. mTOR-regulated senescence and autophagy during reprogramming of somatic cells to pluripotency: a roadmap from energy metabolism to stem cell renewal and aging. Cell Cycle 2011; 10:3658-77; PMID:22052357; http://dx.doi. org/10.4161/cc.10.21.18128
242. Menendez JA, Cufí S, Oliveras-Ferraros C, Vellon L, Joven J, Vazquez-Martin A. Gerosuppressant metformin: less is more. Aging (Albany NY) 2011; 3:348-62; PMID:21483040
243. Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Quirantes R, Segura-Carretero A, Micol V, et al. Metformin lowers the threshold for stress-induced senescence: a role for the microRNA-200 family and miR-205. Cell Cycle 2012; 11:1235-46; PMID:22356767; http://dx.doi.org/10.4161/cc.11.6.19665
244. Vazquez-Martin A, Vellon L, Quirós PM, Cufí S, Ruiz de Galarreta E, Oliveras-Ferraros C, et al. Activation of AMP-activated protein kinase (AMPK) provides a metabolic barrier to reprogramming somatic cells into stem cells. Cell Cycle 2012; 11:974-89; PMID:22333578; http://dx.doi.org/10. 4161/cc.11.5.19450
245. Vazquez-Martin A, Corominas-Faja B, Cufí S, Vellon L, Oliveras-Ferraros C, Menendez OJ, et al. The mitochondrial H (+)-ATP synthase and the lipogenic switch: New core components of metabolic reprogramming in induced pluripotent stem (iPS) cells. [Epub ahead of print]. Cell Cycle 2012; 12; PMID:23287468
246. Lai Y, Yip GW, Bay BH. Targeting metallothionein for prognosis and treatment of breast cancer. Recent Pat Anticancer Drug Discov 2011; 6:178-85; PMID:21449882; http://dx.doi. org/10.2174/157489211795328495
247. Bay BH, Jin R, Huang J, Tan PH. Metallothionein as a prognostic biomarker in breast cancer. Exp Biol Med (Maywood) 2006; 231:1516-21; PMID:17018874
248. Eckschlager T, Adam V, Hrabeta J, Figova K, Kizek R. Metallothioneins and cancer. Curr Protein Pept Sci 2009; 10:360-75; PMID:19689357; http://dx.doi.org/10.2174/138920309788922243
249. Pedersen MØ, Larsen A, Stoltenberg M, Penkowa M. The role of metallothionein in oncogenesis and cancer prognosis. Prog Histochem Cytochem 2009; 44:29-64; PMID:19348910; http://dx.doi. org/10.1016/j.proghi.2008.10.001
250. Nielsen AE, Bohr A, Penkowa M. The Balance between Life and Death of Cells: Roles of Metallothioneins. Biomark Insights 2007; 1:99-111; PMID:19690641
251. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007; 1:555-67; PMID:18371393; http://dx.doi.org/10.1016/j.stem.2007.08.014
252. Eirew P, Kannan N, Knapp DJ, Vaillant F, Emerman JT, Lindeman GJ, et al. Aldehyde dehydrogenase activity is a biomarker of primitive normal human mammary luminal cells. Stem Cells 2012; 30:344-8; PMID:22131125; http://dx.doi.org/10. 1002/stem.1001
253. Marcato P, Dean CA, Pan D, Araslanova R, Gillis M, Joshi M, et al. Aldehyde dehydrogenase activity of breast cancer stem cells is primarily due to isoform ALDH1A3 and its expression is predictive of metastasis. Stem Cells 2011; 29:32-45; PMID:21280157; http://dx.doi.org/10.1002/stem.563
254. Marcato P, Dean CA, Giacomantonio CA, Lee PW. Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle 2011; 10:1378-84; PMID:21552008; http://dx.doi.org/10.4161/cc.10.9.15486
255. Hershko DD. Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer. Cancer 2008; 112:1415-24; PMID:18260093; http://dx.doi.org/10.1002/cncr.23317
256. Chan CH, Lee SW, Wang J, Lin HK. Regulation of Skp2 expression and activity and its role in cancer progression. Scientific World Journal 2010; 10:1001-15; PMID:20526532; http://dx.doi.org/10.1100/tsw.2010.89
257. Wang Z, Fukushima H, Inuzuka H, Wan L, Liu P, Gao D, et al. Skp2 is a promising therapeutic target in breast cancer. Front Oncol 2012; 1:18702; PMID:22279619; http://dx.doi.org/10.3389/fonc.2011.00057
258. Wang Z, Inuzuka H, Zhong J, Liu P, Sarkar FH, Sun Y, et al. Identification of acetylation-dependent regulatory mechanisms that govern the oncogenic functions of Skp2. Oncotarget 2012; 3:1294-300; PMID:23230084
259. Lin HK, Chen Z, Wang G, Nardella C, Lee SW, Chan CH, et al. Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature 2010; 464:374-9; PMID:20237562; http://dx.doi.org/10.1038/nature08815
260. Huang HC, Lin CL, Lin JK. 1,2,3,4,6-penta-Ogalloyl-β-D-glucose, quercetin, curcumin and lycopene induce cell-cycle arrest in MDA-MB-231 and BT474 cells through downregulation of Skp2 protein. J Agric Food Chem 2011; 59:6765-75; PMID:21598989; http://dx.doi.org/10.1021/jf201096v
261. kip1 in E2-stimulated MCF-7 cells through down-regulation of the Skp2 protein. Endocrinology 2008; 149:5972-83; PMID:18719023; http://dx.doi. org/10.1210/en.2008-0408
262. (Kip1)/Skp2 complex. J Agric Food Chem 2011; 59:1996-2003; PMID:21299246; http://dx.doi.org/10.1021/jf103656v
263. Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell 2008; 13:472-82; PMID:18538731; http://dx.doi.org/10.1016/j. ccr.2008.05.005
264. Everse J, Kaplan NO. Lactate dehydrogenases: structure and function. Adv Enzymol Relat Areas Mol Biol 1973; 37:61-133; PMID:4144036
265. Fantin VR, St-Pierre J, Leder P. Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell 2006; 9:425-34; PMID:16766262; http://dx.doi.org/10.1016/j.ccr.2006. 04.023
266. Koukourakis MI, Giatromanolaki A, Simopoulos C, Polychronidis A, Sivridis E. Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer. Clin Exp Metastasis 2005; 22:25-30; PMID:16132575; http://dx.doi.org/10.1007/s10585-005-2343-7
267. Serganova I, Rizwan A, Ni X, Thakur SB, Vider J, Russell J, et al. Metabolic imaging: a link between lactate dehydrogenase A, lactate, and tumor phenotype. Clin Cancer Res 2011; 17:6250-61; PMID:21844011; http://dx.doi.org/ 10.1158/1078-0432.CCR-11-0397
268. Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, et al. Ketones and lactate increase cancer cell "stemness," driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics. Cell Cycle 2011; 10:1271-86; PMID:21512313; http://dx.doi.org/10.4161/cc.10.8.15330
269. Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, et al. Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle 2011; 10:1772-83; PMID:21558814; http://dx.doi. org/10.4161/cc.10.11.15659
270. Balliet RM, Capparelli C, Guido C, Pestell TG, Martinez-Outschoorn UE, Lin Z, et al. Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection. Cell Cycle 2011; 10:4065-73; PMID:22129993; http://dx.doi.org/10.4161/cc.10.23.18254
271. Guido C, Whitaker-Menezes D, Capparelli C, Balliet R, Lin Z, Pestell RG, et al. Metabolic reprogramming of cancer-associated fibroblasts by TGF-β drives tumor growth: connecting TGF-β signaling with "Warburg- like" cancer metabolism and L-lactate production. Cell Cycle 2012; 11:3019-35; PMID:22874531; http://dx.doi.org/10.4161/cc.21384
272. Guido C, Whitaker-Menezes D, Lin Z, Pestell RG, Howell A, Zimmers TA, et al. Mitochondrial fission induces glycolytic reprogramming in cancerassociated myofibroblasts, driving stromal lactate production, and early tumor growth. Oncotarget 2012; 3:798-810; PMID:22878233
273. Carito V, Bonuccelli G, Martinez-Outschoorn UE, Whitaker-Menezes D, Caroleo MC, Cione E, et al. Metabolic remodeling of the tumor microenvironment: migration stimulating factor (MSF) reprograms myofibroblasts toward lactate production, fueling anabolic tumor growth. Cell Cycle 2012; 11:3403-14; PMID:22918248; http://dx.doi. org/10.4161/cc.21701
274. Walenta S, Mueller-Klieser WF. Lactate: mirror and motor of tumor malignancy. Semin Radiat Oncol 2004; 14:267-74; PMID:15254870; http://dx.doi. org/10.1016/j.semradonc.2004.04.004
275. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324:1029-33; PMID:19460998; http://dx.doi. org/10.1126/science.1160809
276. Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci U S A 2010; 107:2037-42; PMID:20133848; http://dx.doi.org/10.1073/pnas.0914433107
277. Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, et al. A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 2008; 3:e2264; PMID:18523577; http://dx.doi.org/10.1371/journal. pone.0002264
278. Huang W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res 2009; 37:1-13; PMID:19033363; http://dx.doi. org/10.1093/nar/gkn923
279. Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009; 4:44-57; PMID:19131956; http://dx.doi. org/10.1038/nprot.2008.211
280. Wietzke JA, Welsh J. Phytoestrogen regulation of a Vitamin D3 receptor promoter and 1,25-dihydroxyvitamin D3 actions in human breast cancer cells. J Steroid Biochem Mol Biol 2003; 84:149-57; PMID:12710998; http://dx.doi.org/10. 1016/S0960-0760(03)00024-4
281. Boissy P, Andersen TL, Abdallah BM, Kassem M, Plesner T, Delaissé JM. Resveratrol inhibits myeloma cell growth, prevents osteoclast formation, and promotes osteoblast differentiation. Cancer Res 2005; 65:9943-52; PMID:16267019; http://dx.doi. org/10.1158/0008-5472.CAN-05-0651
282. Hayes DP. Resveratrol and vitamin D: significant potential interpretative problems arising from their mutual processes, interactions and effects. Med Hypotheses 2011; 77:765-72; PMID:21840648; http://dx.doi.org/10.1016/j.mehy. 2011.07.033
283. Singh CK, Kumar A, LaVoie HA, DiPette DJ, Singh US. Resveratrol prevents impairment in activation of retinoic acid receptors and MAP kinases in the embryos of a rodent model of diabetic embryopathy. Reprod Sci 2012; 19:949-61; PMID:22534330; http://dx.doi.org/10.1177/1933719112438972
284. Stefanska B, Salamé P, Bednarek A, Fabianowska-Majewska K. Comparative effects of retinoic acid, vitamin D and resveratrol alone and in combination with adenosine analogues on methylation and expression of phosphatase and tensin homologue tumour suppressor gene in breast cancer cells. Br J Nutr 2012; 107:781-90; PMID:21801466; http://dx.doi. org/10.1017/ S0007114511003631
285. Huang C, Ma WY, Goranson A, Dong Z. Resveratrol suppresses cell transformation and induces apoptosis through a p53-dependent pathway. Carcinogenesis 1999; 20:237-42; PMID:10069459; http://dx.doi. org/10.1093/carcin/20.2.237
286. Lu J, Ho CH, Ghai G, Chen KY. Resveratrol analog, 3,4,5,4'- tetrahydroxystilbene, differentially induces pro-apoptotic p53/Bax gene expression and inhibits the growth of transformed cells but not their normal counterparts. Carcinogenesis 2001; 22:321-8; PMID:11181455; http://dx.doi.org/ 10.1093/carcin/22.2.321
287. She QB, Bode AM, Ma WY, Chen NY, Dong Z. Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. Cancer Res 2001; 61:1604-10; PMID:11245472
288. Baek SJ, Wilson LC, Eling TE. Resveratrol enhances the expression of non-steroidal anti-inflammatory drug-activated gene (NAG-1) by increasing the expression of p53. Carcinogenesis 2002; 23:425-34; PMID:11895857; http://dx.doi.org/10.1093/carcin/23.3.425
289. Alkhalaf M. Resveratrol-induced apoptosis is associated with activation of p53 and inhibition of protein translation in T47D human breast cancer cells. Pharmacology 2007; 80:134-43; PMID:17534123; http://dx.doi.org/10.1159/000103253
290. Gosslau A, Pabbaraja S, Knapp S, Chen KY. Transand cis-stilbene polyphenols induced rapid perinuclear mitochondrial clustering and p53-independent apoptosis in cancer cells but not normal cells. Eur J Pharmacol 2008; 587:25-34; PMID:18486125; http://dx.doi.org/10.1016/j.ejphar.2008.03.027
291. Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung RH, Ito K, et al. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol 2004; 287:L774-83; PMID:15180920; http://dx.doi. org/10.1152/ajplung.00110.2004
292. de la Lastra CA, Villegas I. Resveratrol as an antiinflammatory and anti-aging agent: mechanisms and clinical implications. Mol Nutr Food Res 2005; 49:405-30; PMID:15832402; http://dx.doi. org/10.1002/mnfr.200500022
293. Amat R, Solanes G, Giralt M, Villarroya F. SIRT1 is involved in glucocorticoid-mediated control of uncoupling protein-3 gene transcription. J Biol Chem 2007; 282:34066-76; PMID:17884810; http://dx.doi.org/10.1074/jbc. M707114200
294. Das S, Das DK. Anti-inf lammatory responses of resveratrol. Inflamm Allergy Drug Targets 2007; 6:168-73; PMID:17897053; http://dx.doi. org/10.2174/187152807781696464
295. Mattson MP, Cheng A. Neurohormetic phytochemicals: Low-dose toxins that induce adaptive neuronal stress responses. Trends Neurosci 2006; 29:632-9; PMID:17000014; http://dx.doi.org/10.1016/j. tins.2006.09.001
296. Kode A, Rajendrasozhan S, Caito S, Yang SR, Megson IL, Rahman I. Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. Am J Physiol Lung Cell Mol Physiol 2008; 294:L478-88; PMID:18162601; http://dx.doi.org/10.1152/ajplung.00361.2007
297. Rubiolo JA, Mithieux G, Vega FV. Resveratrol protects primary rat hepatocytes against oxidative stress damage: activation of the Nrf2 transcription factor and augmented activities of antioxidant enzymes. Eur J Pharmacol 2008; 591:66-72; PMID:18616940; http://dx.doi.org/10.1016/j.ejphar. 2008.06.067
298. Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, et al. Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 2010; 299:H18-24; PMID:20418481; http://dx.doi. org/10.1152/ajpheart.00260.2010
299. Bishayee A, Barnes KF, Bhatia D, Darvesh AS, Carroll RT. Resveratrol suppresses oxidative stress and inflammatory response in diethylnitrosamine- initiated rat hepatocarcinogenesis. Cancer Prev Res (Phila) 2010; 3:753-63; PMID:20501860; http://dx.doi.org/10.1158/1940-6207.CAPR-09-0171
300. Sahin K, Orhan C, Akdemir F, Tuzcu M, Iben C, Sahin N. Resveratrol protects quail hepatocytes against heat stress: modulation of the Nrf2 transcription factor and heat shock proteins. J Anim Physiol Anim Nutr (Berl) 2012; 96:66-74; PMID:21244525; http://dx.doi.org/10.1111/j.1439-0396.2010.01123. x
301. He X, Wang L, Szklarz G, Bi Y, Ma Q. Resveratrol inhibits paraquat-induced oxidative stress and fibrogenic response by activating the nuclear factor erythroid 2-related factor 2 pathway. J Pharmacol Exp Ther 2012; 342:81-90; PMID:22493042; http://dx.doi.org/10.1124/jpet.112.194142
302. 2 cells. J Agric Food Chem 2012; 60:9180-7; PMID:22917016; http://dx.doi.org/10.1021/jf302831d
303. Pearson KJ, Lewis KN, Price NL, Chang JW, Perez E, Cascajo MV, et al. Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction. Proc Natl Acad Sci U S A 2008; 105:2325-30; PMID:18287083; http://dx.doi.org/10.1073/pnas.0712162105
304. Martín-Montalvo A, Villalba JM, Navas P, de Cabo R. NRF2, cancer and calorie restriction. Oncogene 2011; 30:505-20; PMID:21057541; http://dx.doi. org/10.1038/onc.2010.492
305. Bayram B, Ozcelik B, Grimm S, Roeder T, Schrader C, Ernst IM, et al. A diet rich in olive oil phenolics reduces oxidative stress in the heart of SAMP8 mice by induction of Nrf2-dependent gene expression. Rejuvenation Res 2012; 15:71-81; PMID:22236145; http://dx.doi.org/10.1089/rej.2011.1245
306. Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev 2012; 11:230-41; PMID:22186033; http://dx.doi. org/10.1016/j.arr.2011.12.005
307. Katsiki M, Chondrogianni N, Chinou I, Rivett AJ, Gonos ES. The olive constituent oleuropein exhibits proteasome stimulatory properties in vitro and confers life span extension of human embryonic fibroblasts. Rejuvenation Res 2007; 10:157-72; PMID:17518699; http://dx.doi.org/10.1089/rej.2006.0513
308. Konno K, Hirayama C, Yasui H, Nakamura M. Enzymatic activation of oleuropein: a protein crosslinker used as a chemical defense in the privet tree. Proc Natl Acad Sci U S A 1999; 96:9159-64; PMID:10430912; http://dx.doi.org/10. 1073/pnas.96.16.9159
309. Báidez AG, Gómez P, Del Río JA, Ortuño A. Dysfunctionality of the xylem in Olea europaea L. Plants associated with the infection process by Verticillium dahliae Kleb. Role of phenolic compounds in plant defense mechanism. J Agric Food Chem 2007; 55:3373-7; PMID:17394331; http://dx.doi.org/10.1021/jf063166d
310. Lee OH, Lee BY. Antioxidant and antimicrobial activities of individual and combined phenolics in Olea europaea leaf extract. Bioresour Technol 2010; 101:3751-4; PMID:20106659; http://dx.doi. org/10.1016/j.biortech.2009.12.052
311. Blagosklonny MV. Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program. Cell Cycle 2010; 9:3151-6; PMID:20724817; http://dx.doi.org/10.4161/cc.9.16.13120
312. Blagosklonny MV. NCI's provocative questions on cancer: some answers to ignite discussion. Oncotarget 2011; 2:1352-67; PMID:22267462
313. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, et al. Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle 2011; 10:4230-6; PMID:22107964; http://dx.doi. org/10.4161/cc.10.24.18486
314. Leontieva OV, Blagosklonny MV. Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression. Aging (Albany NY) 2011; 3:1078-91; PMID:22156391
315. Blagosklonny MV. Molecular damage in cancer: an argument for mTOR-driven aging. Aging (Albany NY) 2011; 3:1130-41; PMID:22246147
316. Blagosklonny MV. Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging. Aging (Albany NY) 2012; 4:159-65; PMID:22394614
317. Pospelova TV, Leontieva OV, Bykova TV, Zubova SG, Pospelov VA, Blagosklonny MV. Suppression of replicative senescence by rapamycin in rodent embryonic cells. Cell Cycle 2012; 11:2402-7; PMID:22672902; http://dx.doi.org/ 10.4161/cc.20882
318. Komarova EA, Antoch MP, Novototskaya LR, Chernova OB, Paszkiewicz G, Leontieva OV, et al. Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/-mice. Aging (Albany NY) 2012; 4:709-14; PMID:23123616
319. Comas M, Toshkov I, Kuropatwinski KK, Chernova OB, Polinsky A, Blagosklonny MV, et al. New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53-/-mice by delaying carcinogenesis. Aging (Albany NY) 2012; 4:715-22; PMID:23117593
320. Leontieva OV, Blagosklonny MV. Hypoxia and gerosuppression: the mTOR saga continues. Cell Cycle 2012; 11:3926-31; PMID:22987149; http://dx.doi. org/10.4161/cc.21908
321. Blagosklonny MV. How to save Medicare: the antiaging remedy. Aging (Albany NY) 2012; 4:547-52; PMID:22915707
322. Blagosklonny MV. Prospective treatment of agerelated diseases by slowing down aging. Am J Pathol 2012; 181:1142-6; PMID:22841821; http://dx.doi. org/10.1016/j.ajpath.2012.06.024
323. Lane N, Martin W. The energetics of genome complexity. Nature 2010; 467:929-34; PMID:20962839; http://dx.doi.org/10.1038/nature09486
324. Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 2012; 15:675-90; PMID:22560220; http://dx.doi. org/10.1016/j.cmet.2012.04.003
325. Saunders LR, Sharma AD, Tawney J, Nakagawa M, Okita K, Yamanaka S, et al. miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues. Aging (Albany NY) 2010; 2:415-31; PMID:20634564
326. Pardo PS, Boriek AM. An autoregulatory loop reverts the mechanosensitive Sirt1 induction by EGR1 in skeletal muscle cells. Aging (Albany NY) 2012; 4:456-61; PMID:22820707
327. Purushotham A, Schug TT, Li X. SIRT1 performs a balancing act on the tight-rope toward longevity. Aging (Albany NY) 2009; 1:669-73; PMID:20157548
328. Brooks CL, Gu W. Anti-aging protein SIRT1: a role in cervical cancer? Aging (Albany NY) 2009; 1:278-80; PMID:20157516
329. -/- mice. Aging (Albany NY) 2010; 2:353-60; PMID:20606253
330. Lee J, Kemper JK. Controlling SIRT1 expression by microRNAs in health and metabolic disease. Aging (Albany NY) 2010; 2:527-34; PMID:20689156
331. Yang Z, Ming XF. The vascular SIRT ainty. Aging (Albany NY) 2010; 2:331-2; PMID:20606250
332. Bolasco G, Calogero R, Carrara M, Banchaabouchi MA, Bilbao D, Mazzoccoli G, et al. Cardioprotective mIGF-1/SIRT1 signaling induces hypertension, leukocytosis and fear response in mice. Aging (Albany NY) 2012; 4:402-16; PMID:22691943
333. Halperin-Sheinfeld M, Gertler A, Okun E, Sredni B, Cohen HY. The Tellurium compound, AS101, increases SIRT1 level and activity and prevents type 2 diabetes. Aging (Albany NY) 2012; 4:436-47; PMID:22761194
334. Cantó C, Auwerx J. Interference between PARPs and SIRT1: a novel approach to healthy ageing? Aging (Albany NY) 2011; 3:543-7; PMID:21566260
335. Vinciguerra M, Santini MP, Claycomb WC, Ladurner AG, Rosenthal N. Local IGF-1 isoform protects cardiomyocytes from hypertrophic and oxidative stresses via SirT1 activity. Aging (Albany NY) 2010; 2:43-62; PMID:20228935
336. Schug TT, Li X. Surprising sirtuin crosstalk in the heart. Aging (Albany NY) 2010; 2:129-32; PMID:20375467
337. Ramadori G, Coppari R. Does hypothalamic SIRT1 regulate aging? Aging (Albany NY) 2011; 3:325-8; PMID:21464518
338. Hirschey MD, Shimazu T, Capra JA, Pollard KS, Verdin E. SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2. Aging (Albany NY) 2011; 3:635-42; PMID:21701047
339. Mai A. Identification of specific and semi-specific SIRT inhibitors through computer-aided studies. Aging (Albany NY) 2011; 3:819-20; PMID:21937768
340. Schlicker C, Boanca G, Lakshminarasimhan M, Steegborn C. Structure-based development of novel sirtuin inhibitors. Aging (Albany NY) 2011; 3:852-72; PMID:21937767
341. Banerjee KK, Ayyub C, Sengupta S, Kolthur-Seetharam U. dSir2 deficiency in the fatbody, but not muscles, affects systemic insulin signaling, fat mobilization and starvation survival in flies. Aging (Albany NY) 2012; 4:206-23; PMID:22411915
342. Naiman S, Kanfi Y, Cohen HY. Sirtuins as regulators of mammalian aging. Aging (Albany NY) 2012; 4:521-2; PMID:22915706
343. Antosh M, Fox D, Helfand SL, Cooper LN, Neretti N. New comparative genomics approach reveals a conserved health span signature across species. Aging (Albany NY) 2011; 3:576-83; PMID:21775776
344. Froy O, Miskin R. Effect of feeding regimens on circadian rhythms: implications for aging and longevity. Aging (Albany NY) 2010; 2:7-27; PMID:20228939
345. Borrás C, Monleón D, López-Grueso R, Gambini J, Orlando L, Pallardó FV, et al. Ras Grf1 deficiency delays aging in mice. Aging (Albany NY) 2011; 3:262-76; PMID:21422498
346. Vendrell A, Posas F. Sir2 plays a key role in cell fate determination upon SAPK activation. Aging (Albany NY) 2011; 3:1163-8; PMID:22245992
347. Zhang D, Liu Y, Chen D. SIRT-ain relief from ageinducing stress. Aging (Albany NY) 2011; 3:158-61; PMID:21307404
348. Ha CW, Huh WK. The implication of Sir2 in replicative aging and senescence in Saccharomyces cerevisiae. Aging (Albany NY) 2011; 3:319-24;:21415463
349. Tucci P. Caloric restriction: is mammalian life extension linked to p53? Aging (Albany NY) 2012; 4:525-34; PMID:22983298
350. Burks TN, Cohn RD. One size may not fit all: antiaging therapies and sarcopenia. Aging (Albany NY) 2011; 3:1142-53; PMID:22184279
351. Panieri E, Toietta G, Mele M, Labate V, Ranieri SC, Fusco S, et al. Nutrient withdrawal rescues growth factor-deprived cells from mTOR-dependent damage. Aging (Albany NY) 2010; 2:487-503; PMID:20739737
352. Vazquez-Martin A, Cufi S, Lopez-Bonet E, Corominas-Faja B, Oliveras-Ferraros C, Martin-Castillo B, et al. Metformin limits the tumourigenicity of iPS cells without affecting their pluripotency. Sci Rep 2012; 2:964; PMID:23236586; http://dx.doi.org/10.1038/srep00964
353. Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, et al. AMPK Is a Negative Regulator of the Warburg Effect and Suppresses Tumor Growth In vivo. Cell Metab 2012; In press; PMID:23274086
354. Mariño G, Ugalde AP, Salvador-Montoliu N, Varela I, Quirós PM, Cadiñanos J, et al. Premature aging in mice activates a systemic metabolic response involving autophagy induction. Hum Mol Genet 2008; 17:2196-211; PMID:18443001; http://dx.doi. org/10.1093/hmg/ddn120
355. Mariño G, López-Otín C. Autophagy and aging: new lessons from progeroid mice. Autophagy 2008; 4:807-9; PMID:18612261