1. Micronutrient Research for Optimum Health:13 Years and Counting as Primus Inter Pares of the Linus Pauling Institute Balz Frei, Ph.D. Director and Endowed Chair Linus Pauling Institute Oregon State University Corvallis, OR 97331
2. The Evolution of LPI at OSUFrom ½ PI in 1996 to 12 PIs and 4 RAPs today Number of PIs and RAPs
3. Orthomolecular MedicineThe right molecule at the right concentration “Orthomolecular medicine is the preservation of good health and the treatment of disease by varying the concentrations in the human body of substances that are normally present in the body and required for health.” Linus Pauling (1986) “How to Live Longer and Feel Better”
10. Percentage of major chronic diseases in U.S. that is potentially preventable by diet and lifestyle modifications Lung cancer: 90% caused by smoking Willett, WC. Science 2002; 296, 695-698
20. Mechanisms of antioxidant action in atherosclerosis Cell-specific antioxidant action Diaz, Frei et al.New Engl. J. Med. 1997;337:408-416 Total Citations: 774 (#5)
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24. How effectively do the endogenous antioxidants in human plasma (vitamin C, uric acid, bilirubin) and LDL (vitamin E) prevent lipid peroxidation and oxidative (atherogenic) modification of LDL?
53. Vitamin C and E supplementation prevents the increase in plasma F2-isoprostanes following a 50-km ultramarathon Supplementation with 300 mg RRR-α-tocopheryl acetate and 1000 mg vitamin C daily for 21 days Mastaloudis et al. (2004) Free Radic Biol Med. 36:1329-41.
68. Visit One: blood pressure measured at baseline and 2 hours after 2 grams of ascorbic acid
69. Visit Two: blood pressure measured after 30 days of 500 mg/day of ascorbic acidDuffy et al.Lancet 1999;354:2048-2049
70. Plasma Vitamin C correlates with Unstable Coronary Syndrome (Angina Class) in CAD Patients (n = 149) Angina Class (1-4) Antioxidant Marker (Plasma) R P a-Tocopherol -.06 .68 a-Tocopherol (LDL) -.18 .27 g-Tocopherol -.08 .56 b-Carotene .07 .66 Lycopene -.01 .95 Retinol -.15 .36 Ascorbic Acid -.43 .001 Uric Acid .20 .12 Thiols -.19 .15 Ceruloplasmin .00 .97 Superoxide Dismutase (RBCs) -.08 .64 Lag Phase (LDL Diene Conjugation) -.13 .43 F2-Isoprostanes .02 .87 Vita et al. (1998) J. Am. Coll. Cardiol. 31, 980-986
71. Working ModelVitamin CO2l- + NOl___//ONOO- NOl(k2 = 1.9 x 1010 M-1 s-1) (~ 0.1 µM) O2l- Ascorbic Acid (k2 = 2 x 105 M-1 s-1) (~ 0.1 µM x 105 = 10 mM)
72. Oxidation, Enzyme Turnover O O H OH OH N N HN N OH OH Ascorbate H2N H2N N N N N H H Tetrahydrobiopterin (BH4) Quinoid dihydrobiopterin (QBH2) Mechanism of Ascorbate Action
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75. CVD is an inflammatory disease Relative Risk of Cardiovascular Events among Apparently Healthy Postmenopausal Women According to Base-Line Levels of Total Cholesterol and Markers of Inflammation. Each marker of inflammation improved risk-prediction models based on lipid testing alone, an effect that was strongest for hs-CRP and serum amyloid A. Ridker et al. (2000) N Engl J Med 342:836–843
76. The serum concentration of circulating VCAM-1 correlates with angiographically determined athero-sclerotic area in 52 patients with peripheralarterial vascular disease. The solid line represents the regression line (r=0.8, P<.001); the dotted lines represent the 95% confidence interval. Peter, K. et al., Arteriosclerosis, Thrombosis, and Vascular Biology 1997;17:505-512
77. Role of endothelial adhesion molecules and MCP-1 in arterial monocyte/macrophage recruitment and atherosclerosis Monocyte adherence to endothelium ICAM-1 E-selectin Libby (2002) Nature 420:868-874
78. NF-kB as an inflammatory regulator (NOX) IkB kinase IkB P UbUbUbUb IkB Barnes & Karin, NEJM, 1997, 336, 1066
89. Lipoic acid inhibits body weight gain in apoE-/- and apoE/LDLR-/- mice Zhang et al. (2008) Circulation 117:421-428
90. Nature Medicine 10, 727-733 (2004) Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinaseMin-Seon Kim et al.
91. Lipoic acid lowers triglycerides in serum and in VLDL and LDL of apoE-/- and apoE/LDLR-/- mice VLDL LDL HDL Zhang et al. (2008) Circulation 117:421-428
92. Lipoic acid inhibits aortic gene expression of adhesion molecules, cytokines, and CD68 in apoE/LDLR-/- mice Zhang et al. (2008) Circulation 117:421-428
93. En face aortic atherosclerotic lesion analysis in apoE-/- and apoE/LDLR-/- mice (aortic arch and thoracic and abdominal aorta) Control LA- treated ApoE-/- ApoE/LDLR-/- Zhang et al. (2008) Circulation 117:421-428
94. Lipoic acid inhibits aortic atherosclerosis (by 55% and 40%, respectively) in apoE-/- and apoE/LDLR-/- mice Zhang et al. (2008) Circulation 117:421-428
96. Suna (left, 13 yrs old, 22.5 mg/kg/day of (R)-a-lipoic acid for 7 years) and her niece, Willow (right, 3 yrs) Slide courtesy of David Carlson, GeroNova Research Inc
97. Center of Excellence for Research on CAM Antioxidant Therapies (CERCAT) (5P01AT002034-08, Frei)
