Apple Polyphenols and LongevityApril 2012
By George Randall
Apple Polyphenols Prevent Colon Cancer by Multiple Mechanisms
Colorectal cancer is the second leading cause of cancer-related deaths in the United States and the third most common cancer in men and in women.38 Apple polyphenols reach the colon in large concentrations, and they show great promise in reducing the burden of this common disease.39 Indeed, large-scale epidemiological studies show that those who consume larger amounts of apple polyphenols can cut their colon cancer risk by nearly 50%.40
Apple polyphenols act by multiple mechanisms against multiple targets in the toxic environment of the colon. They reduce the substantial oxidant stress under which colon cells must survive, and they scavenge oxygen free radicals, a potent means of reducing cellular and DNA damage.41-43 They also enhance production of natural antioxidant enzymes that colon cells use to protect themselves.44-47
Inflammation typically follows oxidant damage, and is a key event in promoting colon cancer. Apple polyphenols inhibit enzyme systems known as cyclooxygenase and lipoxygenase, both of which produce inflammatory cytokines.41,43,48-51 Apple polyphenols also enhance the rate at which your normal colonic bacteria produce the anti-inflammatory molecule butyrate from dangerous long-chain fats.27,52,53 Butyrate is natural protective element against colon cancer and inflammatory bowel disease.54,55
Many colon cancers are triggered by ingestion of carcinogens in the diet; apple polyphenols promote expression and activity of a range of vital detoxification enzyme systems.45,56 Those systems are essential in preventing carcinogenic chemicals from further damaging cells.
Oxidation, inflammation, and toxins all ultimately produce damage to DNA, which is a first step in formation of cancerous cells. Apple polyphenols show powerful protection of colon cells’ DNA.46,57
Even once a cancer has formed, animal studies have shown that apple polyphenols can slow or stop its growth through several mechanisms. They block the chemical receptors for a molecule called epidermal growth factor, needed by tumor cells to continue their development.58 Apple polyphenols have also been shown to reactivate tumor suppressor genes that have been switched off in cancerous cells, restoring their ability to regulate their growth safely.59 And they induce the cellular suicide mechanism called apoptosis, which is also often switched off in tumor tissues.60,61
The end result of all these actions is to reduce the out-of-control growth typical of cancerous tissue.42 In the lining of the colon, where tumors begin, this is manifested by a reduction of up to 50% in so-called aberrant crypt foci, the pre-cancerous lesions often found on colonoscopy.48,62 And apple polyphenols reduce the numbers of actual pre-cancerous polyps by up to 42% and their growth rate by as much as 60% in animal models.63
Apple Polyphenols Lower Blood Glucose, Prevent Glycation Damage
Even very small blood sugar elevations, especially those immediately following a meal, are now known to be a major cause of tissue damage, even in those who are not diabetic.64 Glucose, though a vital fuel for life, has substantial toxic effects on your body’s proteins over the long haul, producing damaging advanced glycation endproducts (AGEs). Once again, apple polyphenols can help.
Apple polyphenols, especially the unique molecule phloridzin, prevent uptake of glucose from the intestinal tract.15, 65 They do this by inhibiting certain specific glucose transport molecules in the intestinal lining.15,65-68 Animal studies demonstrate significant reductions in overall blood sugar levels.13,64,69 One such study also showed that apple polyphenols completely abolished the after-meal surge of blood sugar levels that’s known to be so dangerous.70
Apple polyphenols also act to block the formation of advanced glycation endproducts, protecting cells from their damaging effects and from the inflammation that can follow.19,75 Furthermore, apple polyphenols scavenge dangerous dicarbonyl molecules that promote glycation and accelerate aging.3,14
Most Life Extension members take nutrients like carnosine, benfotiamine, and pyridoxal-5-phosphate to inhibit deadly glycation reactions, but as already described in this article, apple polyphenols have unique beneficial properties that extend beyond their anti-glycation effects.
Apple Polyphenols Boost Immunity, Fight Infection
Infections are all too often the cause of an untimely death in older people, even in today’s world of antibiotics. Apple polyphenols are powerful natural antimicrobial agents, and are showing great promise in arresting some of the most threatening infections.
Apple polyphenols bind to toxins produced by the bacterium Staph aureus, inactivating them and preventing their deleterious effects.71 Those effects include deadly conditions such as toxic shock syndrome and massive food poisoning, which is common.72 The polyphenols are also active against other common bacterial infections such as Pseudomonas and Bacillus species, and against so-called “atypical” tuberculosis infections.73, 74
The bacterium Helicobacter pylori is the cause of gastritis and stomach ulcers. Apple polyphenols inhibit not only the organism’s growth, but also its ability to bind to stomach lining cells, and its ability to promote inflammation.75 These effects have the potential to prevent recurrence of the bacterial infection and its results after conventional medical treatment.
Of greatest interest is the recent discovery that apple polyphenols can protect animals infected with the deadly H1N1 influenza virus, a potential cause of death among elderly people. Stressed animals with the flu died much sooner than did control animals, but those treated with apple polyphenols survived at much higher rates and lived longer.76
Apples, and especially their skins, are among the fruits richest in the specialized molecules called polyphenols. Apple polyphenols, found in high quantities in the apple’s skin, exert powerful antioxidant, anti-inflammatory, and anti-glycation effects. Together, these effects combine to protect your body from many of the reversible consequences of aging. Compelling evidence exists for apple polyphenols’ ability to prevent, and even reverse changes that produce cardiovascular disease, cancer, elevated blood sugar, and even serious infections.
Since health conscious people today obtain a wide range of polyphenols (such as green tea and pomegranate extracts), a daily dose of 300 mg to 600 mg of apple polyphenols may be all that is needed to obtain desired benefits.
If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.
1. Sunagawa T, Shimizu T, Kanda T, Tagashira M, Sami M, Shirasawa T. Procyanidins from apples (Malus pumila Mill.) extend the life span of Caenorhabditis elegans. Planta Med. 2011 Jan;77(2):122-7.
2. Xiang L, Sun K, Lu J, et al. Anti-aging effects of phloridzin, an apple polyphenol, on yeast via the SOD and Sir2 genes. Biosci Biotechnol Biochem. 2011;75(5):854-8.
3. Peng C, Chan HY, Huang Y, Yu H, Chen ZY. Apple polyphenols extend the mean life span of Drosophila melanogaster. J Agric Food Chem. 2011 Mar 9;59(5):2097-106.
4. Aksenov V, Long J, Lokuge S, Foster JA, Liu J, Rollo CD. Dietary amelioration of locomotor, neurotransmitter and mitochondrial aging. Exp Biol Med (Maywood). 2010 Jan;235(1):66-76.
5. Auclair S, Chironi G, Milenkovic D, et al. The regular consumption of a polyphenol-rich apple does not influence endothelial function: a randomised double-blind trial in hypercholesterolemic adults. Eur J Clin Nutr. 2010 Oct;64(10):1158-65.
6. Garcia V, Arts IC, Sterne JA, Thompson RL, Shaheen SO. Dietary intake of flavonoids and asthma in adults. Eur Respir J. 2005 Sep;26(3):449-52.
7. Gerhauser C. Cancer chemopreventive potential of apples, apple juice, and apple components. Planta Med. 2008 Oct;74(13):1608-24.
8. Shaheen SO, Sterne JA, Thompson RL, Songhurst CE, Margetts BM, Burney PG. Dietary antioxidants and asthma in adults: population-based case-control study. Am J Respir Crit Care Med. 2001 Nov 15;164(10 Pt 1):1823-8.
9. Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ. 1996 Feb 24;312(7029):478-81.
10. Brat P, George S, Bellamy A, et al. Daily polyphenol intake in France from fruit and vegetables. J Nutr. 2006 Sep;136(9):2368-73.
11. Lotito SB, Frei B. Relevance of apple polyphenols as antioxidants in human plasma: contrasting in vitro and in vivo effects. Free Radic Biol Med. 2004 Jan 15;36(2):201-11.
12. Gosch C, Halbwirth H, Stich K. Phloridzin: biosynthesis, distribution and physiological relevance in plants. Phytochemistry. 2010 Jun;71(8-9):838-43.
13. Najafian M, Jahromi MZ, Nowroznejhad MJ, et al. Phloridzin reduces blood glucose levels and improves lipids metabolism in streptozotocin-induced diabetic rats. Mol Biol Rep. 2011 Dec 14.
14. Shao X, Bai N, He K, Ho CT, Yang CS, Sang S. Apple polyphenols, phloretin and phloridzin: new trapping agents of reactive dicarbonyl species. Chem Res Toxicol. 2008 Oct;21(10):2042-50.
15. Manzano S, Williamson G. Polyphenols and phenolic acids from strawberry and apple decrease glucose uptake and transport by human intestinal Caco-2 cells. Mol Nutr Food Res. 2010 Dec;54(12):1773-80.
16. Ma J, Peng X, Ng KM, Che CM, Wang M. Impact of phloretin and phloridzin on the formation of Maillard reaction products in aqueous models composed of glucose and l-lysine or its derivatives. Food Funct. 2011 Dec 8.
17. Ma J, Peng X, Zhang X, Chen F, Wang M. Dual effects of phloretin and phloridzin on the glycation induced by methylglyoxal in model systems. Chem Res Toxicol. 2011 Aug 15;24(8):1304-11.
18. Gatidis S, Meier A, Jilani K, et al. Phlorhizin protects against erythrocyte cell membrane scrambling. J Agric Food Chem. 2011 Aug 10;59(15):8524-30.
19. Duge de Bernonville T, Guyot S, Paulin JP, et al. Dihydrochalcones: Implication in resistance to oxidative stress and bioactivities against advanced glycation end-products and vasoconstriction. Phytochemistry. 2010 Mar;71(4):443-52.
20. Koch TC, Briviba K, Watzl B, et al. Prevention of colon carcinogenesis by apple juice in vivo: impact of juice constituents and obesity. Mol Nutr Food Res. 2009 Oct;53(10):1289-302.
21. Nagasako-Akazome Y, Kanda T, Ohtake Y, Shimasaki H, Kobayashi T. Apple polyphenols influence cholesterol metabolism in healthy subjects with relatively high body mass index. J Oleo Sci. 2007;56(8):417-28.
22. Akazome Y, Kametani N, Kanda T, Shimasaki H, Kobayashi S. Evaluation of safety of excessive intake and efficacy of long-term intake of beverages containing apple polyphenols. J Oleo Sci. 2010;59(6):321-38.
23. Nakazato K, Song H, Waga T. Effects of dietary apple polyphenol on adipose tissues weights in Wistar rats. Exp Anim. 2006 Jul;55(4):383-9.
24. Nakazato K, Song H, Waga T. Dietary apple polyphenols enhance gastrocnemius function in Wistar rats. Med Sci Sports Exerc. 2007 Jun;39(6):934-40.
25. Sugiyama H, Akazome Y, Shoji T, et al. Oligomeric procyanidins in apple polyphenol are main active components for inhibition of pancreatic lipase and triglyceride absorption. J Agric Food Chem. 2007 May 30;55(11):4604-9.
26. de la Garza AL, Milagro FI, Boque N, Campion J, Martinez JA. Natural inhibitors of pancreatic lipase as new players in obesity treatment. Planta Med. 2011 May;77(8):773-85.
27. Aprikian O, Duclos V, Guyot S, et al. Apple pectin and a polyphenol-rich apple concentrate are more effective together than separately on cecal fermentations and plasma lipids in rats. J Nutr. 2003 Jun;133(6):1860-5.
28. Vidal R, Hernandez-Vallejo S, Pauquai T, et al. Apple procyanidins decrease cholesterol esterification and lipoprotein secretion in Caco-2/TC7 enterocytes. J Lipid Res. 2005 Feb;46(2):258-68.
29. Ogino Y, Osada K, Nakamura S, Ohta Y, Kanda T, Sugano M. Absorption of dietary cholesterol oxidation products and their downstream metabolic effects are reduced by dietary apple polyphenols. Lipids. 2007 Mar;42(2):151-61.
30. Aprikian O, Busserolles J, Manach C, et al. Lyophilized apple counteracts the development of hypercholesterolemia, oxidative stress, and renal dysfunction in obese Zucker rats. J Nutr. 2002 Jul;132(7):1969-76.
31. Nagasako-Akazome Y. Serum cholesterol-lowering effect of apple polyphenols in healthy subjects. J Oleo Sci. 2005;54(3):143-51.
32. Auclair S, Silberberg M, Gueux E, et al. Apple polyphenols and fibers attenuate atherosclerosis in apolipoprotein E-deficient mice. J Agric Food Chem. 2008 Jul 23;56(14):5558-63.
33. Osada K, Suzuki T, Kawakami Y, et al. Dose-dependent hypocholesterolemic actions of dietary apple polyphenol in rats fed cholesterol. Lipids. 2006 Feb;41(2):133-9.
34. Lam CK, Zhang Z, Yu H, Tsang SY, Huang Y, Chen ZY. Apple polyphenols inhibit plasma CETP activity and reduce the ratio of non-HDL to HDL cholesterol. Mol Nutr Food Res. 2008 Aug;52(8):950-8.
35. Kujawska M, Ignatowicz E, Ewertowska M, Markowski J, Jodynis-Liebert J. Cloudy apple juice protects against chemical-induced oxidative stress in rat. Eur J Nutr. 2011 Feb;50(1):53-60.
36. Stangl V, Lorenz M, Ludwig A, et al. The flavonoid phloretin suppresses stimulated expression of endothelial adhesion molecules and reduces activation of human platelets. J Nutr. 2005 Feb;135(2):172-8.
37. Vafa MR, Haghighatjoo E, Shidfar F, Afshari S, Gohari MR, Ziaee A. Effects of apple consumption on lipid profile of hyperlipidemic and overweight men. Int J Prev Med. 2011 Apr;2(2):94-100.
38. Available at: www.cdc.gov/cancer/colorectal/statistics/. Accessed January 6, 2012.
39. Kahle K, Huemmer W, Kempf M, Scheppach W, Erk T, Richling E. Polyphenols are intensively metabolized in the human gastrointestinal tract after apple juice consumption. J Agric Food Chem. 2007 Dec 26;55(26):10605-14.
40. Jedrychowski W, Maugeri U, Popiela T, et al. Case-control study on beneficial effect of regular consumption of apples on colorectal cancer risk in a population with relatively low intake of fruits and vegetables. Eur J Cancer Prev. 2010 Jan;19(1):42-7.
41. Schaefer S, Baum M, Eisenbrand G, Janzowski C. Modulation of oxidative cell damage by reconstituted mixtures of phenolic apple juice extracts in human colon cell lines. Mol Nutr Food Res. 2006 Apr;50(4-5):413-7.
42. He X, Liu RH. Phytochemicals of apple peels: isolation, structure elucidation, and their antiproliferative and antioxidant activities. J Agric Food Chem. 2008 Nov 12;56(21):9905-10.
43. Zessner H, Pan L, Will F, et al. Fractionation of polyphenol-enriched apple juice extracts to identify constituents with cancer chemopreventive potential. Mol Nutr Food Res. 2008 Jun;52 Suppl 1:S28-44.
44. Veeriah S, Balavenkatraman KK, Bohmer F, et al. Intervention with cloudy apple juice results in altered biological activities of ileostomy samples collected from individual volunteers. Eur J Nutr. 2008 Aug;47(5):226-34.
45. Veeriah S, Miene C, Habermann N, et al. Apple polyphenols modulate expression of selected genes related to toxicological defence and stress response in human colon adenoma cells. Int J Cancer. 2008 Jun 15;122(12):2647-55.
46. Miene C, Klenow S, Veeriah S, Richling E, Glei M. Impact of apple polyphenols on GSTT2 gene expression, subsequent protection of DNA and modulation of proliferation using LT97 human colon adenoma cells. Mol Nutr Food Res. 2009 Oct;53(10):1254-62.
47. Soyalan B, Minn J, Schmitz HJ, et al. Apple juice intervention modulates expression of ARE-dependent genes in rat colon and liver. Eur J Nutr. 2011 Mar;50(2):135-43.
48. Barth SW, Fahndrich C, Bub A, et al. Cloudy apple juice decreases DNA damage, hyperproliferation and aberrant crypt foci development in the distal colon of DMH-initiated rats. Carcinogenesis. 2005 Aug;26(8):1414-21.
49. D’Argenio G, Mazzone G, Tuccillo C, et al. Apple polyphenol extracts prevent aspirin-induced damage to the rat gastric mucosa. Br J Nutr. 2008 Dec;100(6):1228-36.
50. Jung M, Triebel S, Anke T, Richling E, Erkel G. Influence of apple polyphenols on inflammatory gene expression. Mol Nutr Food Res. 2009 Oct;53(10):1263-80.
51. Nishizuka T, Fujita Y, Sato Y, et al. Procyanidins are potent inhibitors of LOX-1: a new player in the French Paradox. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87(3):104-13.
52. Sembries S, Dongowski G, Mehrlander K, Will F, Dietrich H. Physiological effects of extraction juices from apple, grape, and red beet pomaces in rats. J Agric Food Chem. 2006 Dec 27;54(26):10269-80.
53. Kosmala M, Kolodziejczyk K, Zdunczyk Z, Juskiewicz J, Boros D. Chemical composition of natural and polyphenol-free apple pomace and the effect of this dietary ingredient on intestinal fermentation and serum lipid parameters in rats. J Agric Food Chem. 2011 Sep 14;59(17):9177-85.
54. Scharlau D, Borowicki A, Habermann N, et al. Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre. Mutat Res. 2009 Jul-Aug;682(1):39-53.
55. Thibault R, Blachier F, Darcy-Vrillon B, de Coppet P, Bourreille A, Segain JP. Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: a transport deficiency. Inflamm Bowel Dis. 2010 Apr;16(4):684-95.
56. Petermann A, Miene C, Schulz-Raffelt G, et al. GSTT2, a phase II gene induced by apple polyphenols, protects colon epithelial cells against genotoxic damage. Mol Nutr Food Res. 2009 Oct;53(10):1245-53.
57. Bellion P, Digles J, Will F, et al. Polyphenolic apple extracts: effects of raw material and production method on antioxidant effectiveness and reduction of DNA damage in Caco-2 cells. J Agric Food Chem. 2010 Jun 9;58(11):6636-42.
58. Kern M, Tjaden Z, Ngiewih Y, et al. Inhibitors of the epidermal growth factor receptor in apple juice extract. Mol Nutr Food Res. 2005 Apr;49(4):317-28.
59. Fini L, Selgrad M, Fogliano V, et al. Annurca apple polyphenols have potent demethylating activity and can reactivate silenced tumor suppressor genes in colorectal cancer cells. J Nutr. 2007 Dec;137(12):2622-8.
60. Kern M, Pahlke G, Balavenkatraman KK, Bohmer FD, Marko D. Apple polyphenols affect protein kinase C activity and the onset of apoptosis in human colon carcinoma cells. J Agric Food Chem. 2007 Jun 27;55(13):4999-5006.
61. Miura T, Chiba M, Kasai K, et al. Apple procyanidins induce tumor cell apoptosis through mitochondrial pathway activation of caspase-3. Carcinogenesis. 2008 Mar;29(3):585-93.
62. Gosse F, Guyot S, Roussi S, et al. Chemopreventive properties of apple procyanidins on human colon cancer-derived metastatic SW620 cells and in a rat model of colon carcinogenesis. Carcinogenesis. 2005 Jul;26(7):1291-5.
63. Fini L, Piazzi G, Daoud Y, et al. Chemoprevention of intestinal polyps in ApcMin/+ mice fed with western or balanced diets by drinking annurca apple polyphenol extract. Cancer Prev Res (Phila). 2011 Jun;4(6):907-15.
64. Azuma K, Kawamori R, Toyofuku Y, et al. Repetitive fluctuations in blood glucose enhance monocyte adhesion to the endothelium of rat thoracic aorta. Arterioscler Thromb Vasc Biol. 2006 Oct;26(10):2275-80.
65. Cermak R, Landgraf S, Wolffram S. Quercetin glucosides inhibit glucose uptake into brush-border-membrane vesicles of porcine jejunum. Br J Nutr. 2004 Jun;91(6):849-55.
66. Johnston K, Sharp P, Clifford M, Morgan L. Dietary polyphenols decrease glucose uptake by human intestinal Caco-2 cells. FEBS Lett. 2005 Mar 14;579(7):1653-7.
67. Chen CH, Hsu HJ, Huang YJ, Lin CJ. Interaction of flavonoids and intestinal facilitated glucose transporters. Planta Med. 2007 Apr;73(4):348-54.
68. Kwon O, Eck P, Chen S, et al. Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. FASEB J. 2007 Feb;21(2):366-77.
69. Takii H, Matsumoto K, Kometani T, Okada S, Fushiki T. Lowering effect of phenolic glycosides on the rise in postprandial glucose in mice. Biosci Biotechnol Biochem. 1997 Sep;61(9):1531-5.
70. Fujita Y, Kojima H, Hidaka H, Fujimiya M, Kashiwagi A, Kikkawa R. Increased intestinal glucose absorption and postprandial hyperglycaemia at the early step of glucose intolerance in Otsuka Long-Evans Tokushima Fatty rats. Diabetologia. 1998 Dec;41(12):1459-66.
71. Choi O, Yahiro K, Morinaga N, Miyazaki M, Noda M. Inhibitory effects of various plant polyphenols on the toxicity of Staphylococcal alpha-toxin. Microb Pathog. 2007 May-Jun;42(5-6):215-24.
72. Rasooly R, Do PM, Friedman M. Inhibition of biological activity of staphylococcal enterotoxin A (SEA) by apple juice and apple polyphenols. J Agric Food Chem. 2010 May 12;58(9):5421-6.
73. Fattouch S, Caboni P, Coroneo V, et al. Comparative analysis of polyphenolic profiles and antioxidant and antimicrobial activities of tunisian pome fruit pulp and peel aqueous acetone extracts. J Agric Food Chem. 2008 Feb 13;56(3):1084-90.
74. Wong SY, Grant IR, Friedman M, Elliott CT, Situ C. Antibacterial activities of naturally occurring compounds against Mycobacterium avium subsp. paratuberculosis. Appl Environ Microbiol. 2008 Oct;74(19):5986-90.
75. Pastene E, Speisky H, Garcia A, Moreno J, Troncoso M, Figueroa G. In vitro and in vivo effects of apple peel polyphenols against Helicobacter pylori. J Agric Food Chem. 2010 Jun 23;58(12):7172-9.
76. He RR, Wang M, Wang CZ, et al. Protective effect of apple polyphenols against stress-provoked influenza viral infection in restraint mice. J Agric Food Chem. 2011 Apr 27;59(8):3730-7.
77. Queen BL, Tollefsbol TO. Polyphenols and aging. Curr Aging Sci. 2010 Feb;3(1):34-42.
78. Weinreb O, Mandel S, Amit T, Youdim MB. Neurological mechanisms of green tea polyphenols in Alzheimer’s and Parkinson’s diseases. J Nutr Biochem. 2004 Sep;15(9):506-16.
79. Akiyama H, Sakushima J, Taniuchi S, et al. Antiallergic effect of apple polyphenols on the allergic model mouse. Biol Pharm Bull. 2000 Nov;23(11):1370-3.
80. Tokura T, Nakano N, Ito T, et al. Inhibitory effect of polyphenol-enriched apple extracts on mast cell degranulation in vitro targeting the binding between IgE and FcepsilonRI. Biosci Biotechnol Biochem. 2005 Oct;69(10):1974-7.
81. Nakano N, Nishiyama C, Tokura T, et al. Procyanidin C1 from apple extracts inhibits Fc epsilon RI-mediated mast cell activation. Int Arch Allergy Immunol. 2008;147(3):213-21.
82. Akiyama H, Sato Y, Watanabe T, et al. Dietary unripe apple polyphenol inhibits the development of food allergies in murine models. FEBS Lett. 2005 Aug 15;579(20):4485-91.
83. Kishi K, Saito M, Saito T, et al. Clinical efficacy of apple polyphenol for treating cedar pollinosis. Biosci Biotechnol Biochem. 2005 Apr;69(4):829-32.
84. Enomoto T, Nagasako-Akazome Y, Kanda T, Ikeda M, Dake Y. Clinical effects of apple polyphenols on persistent allergic rhinitis: A randomized double-blind placebo-controlled parallel arm study. J Investig Allergol Clin Immunol. 2006;16(5):283-9.
85. Akazome Y. Characteristics and physiological functions of polyphenols from apples. Biofactors. 2004;22(1-4):311-4.