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New Findings on antioxidants Super Antioxidants

Taiwan NuSkin presentation Medical Symposium November 3, 2007. New Findings on antioxidants Super Antioxidants. Prof. Lester Packer. US. Western countries. Asian countries. China. Int.J. Cancer (2000) 85:60-7. Courtesy Emily Ho.

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New Findings on antioxidants Super Antioxidants

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  1. Taiwan NuSkin presentation Medical Symposium November 3, 2007 New Findings on antioxidants Super Antioxidants Prof. Lester Packer

  2. US Western countries Asian countries China Int.J. Cancer (2000) 85:60-7 Courtesy Emily Ho

  3. Cross Cultural Study of Heart Disease Mortality

  4. Oxidative Stress • Free radicals cause oxidative stress • Leads to tissue damage, aging and disease

  5. Oxidant burden Oxidant burden ROS formation Redox Signaling Oxidative Stress Damage vs. Repair Adaptive Signaling Apoptotic Signaling Necrosis Oxidative Stress Damage vs. Repair Adaptive Signaling ROS formation Redox Signaling Apoptotic Signaling Necrosis Oxidant induced cell signaling and damage

  6. Oxidative Stress “An imbalance between oxidants and antioxidants in favor of the oxidants, leading to a disruption of redox signaling and control and/or molecular damage.” Jones, D.P. Redefining oxidative stress. Antioxid. Redox Signal. 2006, 8: 1865-1879.

  7. Glutathione is the cell’s major antioxidant 2 GSH + H2O2 GSSG + 2 H2O GSSG + NADPH 2 GSH + NADP+ Oxidative Stress can be estimated from the ratio of reduced to oxidized antioxidants GSH reduced GSSG oxidized Gluthathione Peroxidase Gluthathione Reductase

  8. Ratio of GSH/GSSG becomes progressively oxidized during the life cycle of cells Redox State -(SH)2:-SS- Proliferation 100:1 - - 250 250 Eh, mV 10:1 Differentiation 1:1 - - 200 200 Apoptosis 1:10 - - 150 150 Kirlin WG, Cai J, Thompson SA, Diaz D, Kavanagh TJ, Jones DP. Glutathione redox potential in response to differentiation and enzyme inducers.Free Radic Biol Med. 1999 Dec;27(11-12):1208-18.

  9. Oxidative Stress -80 mV Pathophysiology (-140 mV) -50 mV (-110 mV) Type 2 Diabetes Cigarette Smoking Increased Carotid Intima Media Thickness Reversible myocardial Ischemia perfusion injury -20 mV (-80 mV) Cys/CySS Redox (GSH/GSSG Redox) Jones D.P., Antioxid Redox Signal. 2006 Sep-Oct;8(9-10):1865-79.

  10. Antioxidants Redox • Vitamins C and E • Polyphenols (Flavonoids) • Low molecular weight thiols: • Cysteine, Methionine, Glutathione, R- Lipoic Acid, • Co-enzyme Q • L-Carnitine Radical Scavenging • Carotenoids

  11. The Antioxidant Network in Membranes Vit. E• cycle Q10 H • cycle Carotenoids Oxygen Metabolism Water Soluble Lipid Free Radicals LOO• LO• Fat Soluble Vit. C• cycle Water Soluble Metabolism

  12. Inducers Of Phase 2 enzymes and proteins INDUCER INDUCER S S S S SH SH INDUCER INDUCER Keap 1 or Keap 1 Nrf2 Keap 1 or S S CYTOPLASM Nrf2 Keap 1 small Maf Nrf2 Phase 2 Genes ARE NUCLEUS “The capacity of these compounds to induce the phase 2 response depends upon their ability or that of their metabolites to react with thiol groups, a property shared with all other classes of phase 2 inducers, which show few other structural similarities” Dinkova-Kostova, A.T., Holtzclaw, W.D., Cole, R.N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., Talalay, P., PNAS USA, 99(18):11908-13, 2002. Fahey JW, Stephenson KK, Dinkova-Kostova AT, Egner PA, Kensler TW, Talalay P. Carcinogenesis 2005 Jul;26(7):1247-55

  13. Inducers of Nrf2 transcription, the phase II response, all have in common the ability to react with suphydryl groups Polyphenols Bioflavanoids Chlorophyll Carotenoids Heme, H2O2, NO● Carotenoid oxidation products Chemicals reacting with Sulphydryl groups, e.g., Isothioyonates (sulforaphane), Dithiolanes, 1,2-dithiol-3-thiones, α-Lipoic acid Nrf2-Keap-1system (ARE/EpRE) Alkyl and Aryl Halides, Metal Ions, e.g., HgCl2, CdCl2 HO-l GCL GSH increases NAD(P)H-Quinone reductase, Ferritin, Epoxide hydrolase GSH, Gluconic acid,methyl and other transferases Mn Superoxide Dismutase Thioredoxin, Trx reductase Mitochondrial and other Antioxidant enzymes Antioxidant Defense, Detoxification, Chemoprevention

  14. Carotenoids in Humans are • Vitamin A precursors • cyclic hydrocarbon carotenoids • Free radical scavengers • protect against oxidation • Inducers of enzymes & proteins • needed for antioxidant defense

  15. Carotenoids in fruits & vegetables Carotenoids in Human Plasma Lycopene (20-40%) b -carotene (15-30%) a-carotene (5-10%) β-cryptoxanthin (13-20%) Spinach, Green peas, Green Beans , Lima Beans Broccoli, Brussel sprouts, Cabbage, kale, Kiwi, Lettuce Carrots, Pumpkin, Sweet Potatoes, Apricots, Cantaloupe, Watermelon Tomatoes, Pink Grapefruit Lutein (10-20%) Zeaxanthin (1-5%)

  16. Raman ScatteringSir C. V. Raman, Nobel Prize in Physics 1930 Raman scattered light Laser light Carotenoids shift blue laser light to green: from473 nmto510 nm

  17. Raman scattering studies are used to measure carotenoids in the Eye and to diagnose age-related macular degeneration Lutein & Zeoxanthin Macula Gellermann W, Ermakov IV, McClane RW, Bernstein PS. Raman imaging of human macular pigments. Optics Letters. 2002;27:833

  18. Lifestyle affects raman scattering intensity Skin Raman Intensity (2005 US data of 209,628 Non-Supplement Users) 35000 31507 30000 29704 26639 25000 p<0.01 p<0.01 p<0.01 24793 20000 Std. Error 38 Std. Error 61 Std. Error 106 Std. Error 44 15000 Courtesy Stephen Poole, Pharmanex 10000 1 or less 2 to 3 4 to 5 6 or more Daily servings of fruits and vegetables Skin Raman Intensity (n = 372) 60000 40000 r = 0.84 (p<0.0001) 20000 C. Smidt and D.S. Burke, Nutritional Significance and Measurement of Carotenoids, Current Topics in Nutraceutical Research 2004, 2, 79-91 0 4 0 0.5 1 1.5 2 2.5 3 3.5 Total Serum Carotenoids (μg/ml)

  19. Carotenoids in human supplements equivalent to amounts in food (courtesy KJ Yuem) 4 mg Lycopene 4 mg b-Carotene 4 mg Lutein 1 & 1/3 medium carrots or ¼ cup pumpkin 1 medium tomato or ¾ Tsp tomato paste ¼ cup of cooked spinach

  20. * * * * * * * * * * * * * * * * * * * Plasma Carotenoid Concentration Is increased after Supplementation 180 Placebo Mixed Car 160 Lutein b-Carotene 140 Lycopene 120 100 Plasma Total Carotenoid (mg/dL) 80 60 40 20 0 D1 D15 D29 D43 D57 Time, Day Significantly different from baseline * p<0.05 Courtesy KJ Yuem, et al.

  21. Day 1 (Subject # 35563) Carotenoid Supplementation protects DNA Damage of human lymphocytes The comet assay Day 57 Courtesy KJ Yuem, et al.

  22. Carotenoid Supplementation protects DNA damage in human lymphocytes Lutein Mixed Car Lycopene b-Carotene Comet tail factor ratio compared with day 1 Placebo 1.6 1.4 1.2 1.0 0.8 0.6 0.4 (D1/D1) (D15/D1) (D29/D1) (D43/D1) (D57/D1) Closed symbols indicate significant differences from Placebo group (p<0.05) Courtesy KJ Yuem, et al.

  23. Physiological doses of a β-carotene, lycopene, lutein or a mixture of these carotenoids protect against endogenous or hydrogen peroxide (H2O2 ) induced DNA damage in white human blood cell lymphocytes

  24. Genes effected by carotenoids in lung tissue of cigaraette exposed exposed mice Nrf2 Transcription Growth factors Metabolism and Ion channels Receptors Inflammatory and immune responses Apoptosis Unknown Genes Others Control diet 20 Genes Up or down regulated 0 -20 Β-carotene 20 0 -20 Lycopene 20 0 -20 Lutein 20 0 -20 Mixed 3-Carotenoids 20 0 -20

  25. Gene chip studies show carotenoids… • … have specific effects on gene expression • … effect expression of genes for transcription factors which enhance the biosynthesis of antioxidant enzymes and proteins • … modify genes affecting xenobiotic metabolism and immune system response

  26. Vitamin A levels are increased in healthy centenarians compared to younger subjects 6 153 Italian centenarians, * p < 0.0001 5 4 * * * Vitamin A (µM) 3 2 1 0 60-79 yrs 80-99 yrs Centenarians < 60 yrs Christina Polidori, Eur J Clin Nutr 2007

  27. Super Antioxidants Substances in plant fruits and vegetables have a wide range of different molecular structures. Some like bioflavonoids are powerful direct free radical scavengers. These and other small molecules also can induce the biosynthesis of antioxidants. These are bifunctional antioxidants or “Super Antioxidants” because they… …scavenge free radicals directly and immediately …but also act indirectly by inducing genes and thus have long lasting effects

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