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IABG 2003 Cambridge University, UK Aging, Exercise and Phytochemicals: Promises and Pitfalls

IABG 2003 Cambridge University, UK Aging, Exercise and Phytochemicals: Promises and Pitfalls. Li Li Ji Departments of Kinesiology Intedisciplinary Nutritional Science and Institute on Aging University of Wisconsin-Madison, USA.

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IABG 2003 Cambridge University, UK Aging, Exercise and Phytochemicals: Promises and Pitfalls

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  1. IABG 2003 Cambridge University, UKAging, Exercise and Phytochemicals:Promises and Pitfalls Li Li Ji Departments of Kinesiology Intedisciplinary Nutritional Science and Institute on Aging University of Wisconsin-Madison, USA

  2. Exercise is an important means to keep fit, prevent diseases and improve quality of life, or at least to maintain mobility. ROS generation in Skeletal Muscle

  3. Mitochondrial respiratory Chain increased oxygen consumption produces more O2.- and H2O2. • Xanthine oxidase Insufficient blood flow (hypoxia) leads to degradation of ATP to hypoxanthine producing O2.-and H2O2 . • Neutrophil (PMN) Respiratory burst by NADPH oxidase IL-1, IL-6 and TNF- increases adhesion molecules and PMN infiltration • Lipoxygenase/cycloxygenase Activated by cytokines, hormones and toxins

  4. An acute bout of exercise in rats increases ROS production in skeletal muscle. Aged rats generates more ROS at rest and during exercise (15 m/min, 0%) at the same relative workload as young rats (25 m/min, 10%). Both mitochondria and NADPH oxidase are sources of ROS in young muscle during exercise. For aged muscle, mitochondria seem to be the main source. ROS generation is also increased in the heart. With 2 mM pyruvate and 2 mM malate as mitochondrial respiration substrates Replace pyr- malate wiith 1.7 mM ADP, 0.1 mM NADPH and Fe+3 Ji & Bejma J.A.P. (1999) Source of Free Radicals in Skeletal Muscle

  5. The ability of the cell to resist or prevent oxidative stress is a key determinant of its longevity. - Finkel and Holbrook. Science 2000 Strategies to boost antioxidant defense Caloric restriction Transgene Dietary supplementation Antioxidant mimics Adaptation (Exercise training)

  6. Antioxidant Supplementation • Nature offers rich sources of antioxidants contained mainly in plants (fruits, vegetables and herbs) known as phytochemical antioxidants. • Phenolic compounds are important antioxidants due to their redox properties in absorbing, quenching and decomposing ROS.

  7. IABG 2003 Cambridge University, UK Hypothesis 1: Ginseng supplementation ameliorates age-associated oxidative stress in rats Fu & Ji, J. Nutr. (in press)

  8. Ginseng Antioxidant Property There are two kinds of ginsengs, Panax C. A. Meyer (Asian ginseng) and Panax quinquefolius L. (Wisconsin ginseng) The primary activate ingredients are a mixture of saponin glycosides, known as ginsenosides . Higher ginsenoside content is found in Panax quinquefolius. R1, R2, and R3 may vary between glucose, arabinose and rhamnose and their combination

  9. Ginseng Antioxidant Property Phytopanaxadiols are a group of ginsenosides containing two glucose moieties on C-3 position while differing between glucose and arabinose on C-20 such as Rb1, Rb2, etc. Phytopanaxadiols appear to not only scavenge free radicals and chelate metal ions, but also influence gene expression of antioxidant enzymes. • Rb1 interact with hydroxyl radicals and protect ischemic neuron. Rb2 stimulate nuclear protein biding to gene regulatory sequences on CuZn SOD promoter.

  10. Experimental Design Animals:Female Fischer 344Rats at 8 month (young) and 26 month age (old) Diet:AIN-95 purified diet with 0.5 mg/kg (low dose) or 2.5 mg/kg (high dose) Wisconsin ginseng for 4 months. Ginsenosides (11.95%): Rb1, 1.5; Rb2, 0.02, Rc, 1.67; Rd, 1.86; Re, 3.42; Rg1, 1.09 IABG 2003 Cambridge University, UK

  11. Oxidant production rate (dichlorofluorescin, DCFH as probe) in the homogenate of rat heart and skeletal muscle (deep portion of vastus lateralis). The assay buffer contained 130 mM KCl, 5 mM MgCl2, 20 mM NaH2PO4, 20 mM Tris-HCl, and 30 mM glucose (pH 7.4) with 5 M DCFH-diacetate dissolved in 1.25 mM methanol. Each bar represents mean  SEM with number of rats in each group specified in previous slide. * p<0.05, Low-dose or High-dose ginseng vs. Control. +p<0.05, main age effect; ++ p<0.01, 26 month vs. 8 month old rats. Heart Muscle

  12. Protein carbonyl content in rat heart and skeletal muscle (deep portion of vastus lateralis). Each bar represents mean  SEM. * p<0.05, Low-dose or High-dose ginseng vs. Control. +p<0.05; ++ p<0.01, 26 month vs. 8 month old rats Heart Muscle

  13. Western blot analysis ofReactive carbonyl derivative in the heart and skeletal muscle (deep portion of vastus lateralis) of old rats with control (C), low-dose (L) or high-dose (H) ginseng diet. Heart Muscle H L C H L C 80kD 50kD

  14. Heart Muscle MDA content in rat heart and skeletal muscle (deep portion of vastus lateralis). Each bar represents mean  SEM. * p<0.05, Low-dose vs. or High-dose. +p<0.05; 26 month vs. 8 month old rats

  15. Superoxide dismutase (SOD) activity in rat heart and skeletal muscle (deep portion of vastus lateralis). Each bar represents mean  SEM. * p<0.05, Low-dose or High-dose ginseng vs. Control. +p<0.05; ++ p<0.01, 26 month vs. 8 month old rats Heart Muscle

  16. Glutathione peroxidase (GPX) activity in rat soleus and deep portion of vastus lateralis (DVL) muscle. Each bar represents mean  SEM. * p<0.05, Low-dose or High-dose ginseng vs. Control. +p<0.05; 26 month vs. 8 month old rats Soleus Vastus lateralis

  17. Body wt was not significantly different among three dietary groups of young rats Potential Side-effects Body wt was lower (P<0.01) in high-dose compared to low-dose and control groups of old rats.

  18. Citrate synthase (CS) activity in rat heart and skeletal muscle (deep portion of vastus lateralis). Each bar represents mean  SEM. * p<0.05, Low-dose or High-dose ginseng vs. Control. +p<0.05; ++ p<0.01, 26 month vs. 8 month old rats Heart Muscle

  19. IABG 2003 Cambridge University, UK Summary1: Dietary supplementation of ginseng for 4 months in rats decreased oxidant production and age-related oxidative damage to protein in the heart and skeletal muscle. Elevated SOD and GPX activities may partially explain these protective effects. The effects seem to be dose-dependent. Possible side-effects on growth should be examined.

  20. IABG 2003 Cambridge University, UK Hypothesis 2: Oat antioxidant supplementation attenuates exercise-induced oxidative damage in rats Ji et al. Nutr. Res. (in press)

  21. Oat Antioxidants Oat (Avena sativa L.) contains several families of compounds displaying antioxidant properties. Non-flavonoid phenols Flavonoids

  22. Compositions of the Experimental Diet Ingredient Control Flour Pearling Casein 200.0 125.0 170.2 L-Cystine 3.0 3.0 3.0 Oat Flour0.0500.0 0.0 Oat Pearling 0.0 0.0 200.0 Corn Starch 392.0 46.55 295.7 Maltodextrin 129.49 129.49 129.49 Sucrose 58.0 58.0 58.0 Corn Oil 100.0 64.3 84.1 Cholesterol 10.0 10.0 10.0 Cholic Acid 2.0 2.0 2.0 Cellulose 58.0 14.15 0.0 Mineral Mix (AIN-93-MX) 35.0 35.0 35.0 Vitamin Mix (AIN-93-VX) 10.0 10.5 10.0 Choline bitartrate 2.5 2.5 2.5 TBHQ (Antioxidant) 0.01 0.01 0.01 Total (g) 1000.0 1000.0 1000.0

  23. ROS Production in Muscle *P<0.05 Exercise vs. Rest + P<0.05 Oat vs. Control.

  24. Muscle Glutathione Status GSH GSSG GSH:GSSG Control Rested 0.69 ± 0.03 0.02 ± 0.002 35.1 ± 3.23 Exercised 0.67 ± 0.04 0.03 ± 0.003 + 22.0 ± 1.93 + Oat Flour   Rested 0.75 ± 0.02 0.03 ± 0.002 30.1 ± 2.37 Exercised 0.75 ± 0.04 0.03 ± 0.004 26.8 ± 2.91 + Oat Pearling   Rested 0.71 ± 0.08 0.03 ± 0.002 24.5 ± 3.26 * Exercise 0.67 ± 0.04 0.04 ± 0.003 + 19.6 ± 1.54 + ANOVA, P= * Diet = 0.08 *Diet = 0.026 +Exer = 0.006 +Exer = 0.002

  25. General structure of avenathramides. Variations of R1 and R2 moiety give three classes as Aven. A, B, andC. HPLC chromatographs of Aven. A, B, and C. Oat AntioxidantsAvenathramides are anionic, substituted cinnamic acid conjugates found only in oats that demonstrate high antioxidant potency.

  26. Avenathramide Supplementation Purpose of the Study To investigated the efficacy of dietary supplementation of avenathramides in rats at rest and after an acute bout of oxidative stress imposed by heavy exercise Hypotheses • Avenathramide supplementation increases endogenous antioxidant defense capacity • Avenathramide supplementation decreases intracellular ROS generation at rest and during exercise • Avenathramide supplementation decreases tissue oxidative damage at rest and after exercise

  27. Study Design • Animals:Female Sprague-Dawley rats (n=48, age 6-7 wk) • Diet: AIN-93 based control diet or a diet containing 0.1 g/kg AVEN Bc (N-3’,4’-dihydroxycinnamoyl)-5-hydroxyanthranilic acid) 50 days. • Exercise: Treadmill running at 22.5 m/min, 10% grade for 1 hour. • Tissue Collection: Heart, liver, kidney, Deep vastus lateralis (DVL) and soleus muscle.

  28. Body weight of the rats was not different among various treatment groups at the beginning or the end of the experiments. Food consumption showed no difference between groups of rats. Final Body Weight of Rats

  29. ROS Production Exercise increased ROS in the liver. Aven did not affect ROS generation. Aven increased ROS generation (P<0.05) in the heart of exercise rats.

  30. Aven attenuated exercise induced ROS (P<0.05) in soleus muscle. ROS generation in DVL muscle was increased (P<0.1) with exercise. No Aven effect was found. ROS generation

  31. Aven increased SOD activity in theliver(P<0.01). SOD Activity Aven increased SOD activity in thekidney(P<0.01).

  32. Aven decreasedSOD activity in theheart(P<0.05) of exercise rats. Aven increased SOD activity in the DVL muscle (P<0.01). SOD Activity

  33. Exercise increased GPX activity in the liver(P<0.05). Aven had no effect on GPX activity. GPXactivity tended to be higher (P<0.09) in the heart of Aven vs. Control rats. GPX Activity

  34. GPXactivity was not affected by Aven or exercise inKidney or DVL muscle. GPX Activity

  35. Exercise increased MDAcontent in the liver(P<0.05). Aven did not affect exercise-induced lipid peroxidation. Exercise increased MDA content in theheart (P<0.01). Aven attenuated exercise-induced lipid peroxidation (P<0.05). Lipid Peroxidation

  36. Lipid Peroxidation • Exercise increased MDA content in DVL muscle (P<0.05). No Aven effect. • MDA content was not changed in kidney with Aven or exercise.

  37. IABG 2003 Cambridge University, UK Summary 2 Aven appears to be a potential antioxidant supplement as it decreased ROS generation in oxidative muscle soleus and increased SOD activity in most tissues. The wide tissue-specific and sometimes adverse effects are currently unexplained and require further investigation.

  38. IABG 2003 Cambridge University, UK Conclusion Phytochemicals offer a wide-spectrum of antioxidant properties ranging from scavenging ROS to increasing antioxidant enzymes in various tissues In vitro and in vivo. They can provide protective effects against age- and exercise-induced oxidative damage. Except for a few well-defined ones, we still know little about the bioavailability, tissue distribution, dose response and potential side effects of most phytochemicals.

  39. IABG 2003 Cambridge University, UK Acknowledgment Ying Fu, MS David Lay, MS Euhee Chung, MS Stacey Brickson, Ph.D. David Peterson, Ph.D. USDA CSREES grant UW UIR grant Kaiser Farms, Inc. for ginseng supply Now Foods Inc. for travel support

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