1. Stress and the Aging Heart PD Dr. Klara Brixius Department of Molecular and Cellular Sport Medicine (Head: Prof. Dr. W. Bloch) Institute of Cardiology and Sport Medicine German Sport University Cologne

2. ‚Aging‘ Getting older Getting old Cellular Growth/Regeneration Degeneration/Senescence Stress and the Aging Heart

3. Cardiac Stress Oxidative Stress

4. Stress and the Aging Heart ‚Oxidative Stress‘ and Antioxidant Defense Mechanisms Gender Differences in the Aging Heart, Prevention and Therapeutic Consequences

5. Oxidative Stress : Definition O 2 O O O O Superoxide Anion O2O2 O O Oxygen Molecule

6. Oxidative Enzymes : Cytochrome C Oxidase Oxidative Phosphorylation Inner Side Matrix Outer Side Intermembraneous Space

7. Oxidative Enzymes : NAD(P)H-Oxidases

8. Oxidative Enzymes : Xanthine-Oxidases Modified from Tossios and Mehlhorn 2004, Blickpunkt der Mann 2: 36-39 Physical Exercise Ischemia ATP ADP Adenosine Hypoxanthine Xanthine oxidase Xanthine + O 2 Xanthine oxidase O 2 + Urate

9. ROS and the Aging Heart Lipid peroxidation (cellular membranes) Protein oxidation (Cytosol) DNA oxidation (Nucleus) Cellular Dysfunction ROS and the Aging Heart Cellular Dysfunction Hyperglycemia Angiotension, etc. oxLDL Cardivascular Risk Factors Webside Prof. S. Harding Imperial College London

10. ROS and the Aging Heart modified from Brandes et al. Cardiovasc Res (2005) 66: 286-294 Tissue Degeneration Hyperglycemia Angiotension, etc. oxLDL Cardivascular Risk Factors

11. Oxidative Stress : Definition Antioxidative Defense ROS

12. Radical Buffer Systems: Vitamines Thioredoxins/Peroxiredoxins Proteins (Albumin, Thiols) ROS and Antioxidative Defense Mechanisms O2O2 O2O2 H2O2H2O2 OH H2OH2O 1O21O2 SOD (Mn, Cu) Katalase Cytochrome C Oxidase NAD(P)H Oxidase Xanthin Oxiase Gluthatione Peroxidase (Se, GSH)

13. * 0 1 2 3 4 5 n=6 n=6 n=9 n=9 8-Isoprostan Strassburger et al. Free Radical Biology & Medicine (2005) 38: 1458-1470 No increase in the vessel/myocyte ratio in MnSOD-knockout mice after endurance training Vessel/myocyte Con Train Con Train Brixius, Bloch et al. 2006, in preparation * *: p<0.05 MnSOD-KNO Wild type MnSOD-KNO

14. Adaptation of Antioxidative Defense Mechanisms modified from Gutteridge 1992, Free Rad Res Comm 19: 598-620 Adaptation Antioxidants Oxidative Stress Maladaptation

15. Differential Down-Regulation of Peroxiredoxin Isoforms in Human Failing Myocardium Peroxiredoxin 1Peroxiredoxin 2Peroxiredoxin 3 Peroxiredoxin 4Peroxiredoxin 5 Peroxiredoxin 6 NFDCM 0 10 20 30 40 50 60 70 80 NFDCM 0 30 60 90 120 150 180 210 240 DU/µg prot. NF n=6 DCM NFDCM 0 20 40 60 80 100 120 DU/µg prot. NFDCM p=0.08 0 5 10 15 20 25 30 35 DU/µg prot. p=0.06 NFDCMNFDCM 0 10 20 30 40 50 p=0.07 DU/µg prot. NFDCM NFDCM NFDCM 0 4 8 12 16 20 DU/µg prot. p=0.06 NFDCM NFDCM Number of experiments,NF and DCM: n=6 each Brixius, Bloch, 2006, in preparation

16. Stress and the Aging Heart ‚Oxidative Stress‘ and Antioxidant Defense Mechanisms Gender Differences in the Aging Heart Therapeutic Consequences ?

17. Stress and the Aging Heart: Gender Vina et al. 2005, FEBS Letters 579: 2541-2545

18. Antioxidative Mechanisms of Estrogenes Non genomic Rapid Genomic Slow Estrogen Antioxidative Enzymes  ER Estrogen ERE ER Oxidative Defense 

19. De Simone et al., Hypertension 31: 1077-1082, 1998 Gender-Specific Differences in Cardiac Function Men (n = 229) Women (n = 164) Age, y 46 ± 12 44 ± 13 Body weight, kg 74 ± 8 61 ± 9§ Body height, m 1.75 ± 0.08 1.62 ± 0.07 § Heart rate, bpm66 ± 1169 ± 11 Blood pressure, mm Hg121/75 ± 9/7114/70 ± 12/8 + LV mass, g 155 ± 33 111 ± 25§ Stroke volume, ml/beat 78 ± 16 64 ± 12§ Stroke work, g-m/beat136.15 ± 30.38105.21 ± 25.06§ *P<05; +P<005; §P<0001 for gender difference within age stratum.

20. Stroke Work/LV Mass, g-m/beat per gram Stroke Work Index/LV Mass, g-m/beat/m 2 per gram 0.89 ± 0.170.47 ± 0.1 * Men (n = 229) Women (n = 164) 0.97 ± 0.230.59 ± 0.15 * De Simone et al., Hypertension 31: 1077-1082, 1998 Ratio of Stroke Work to LV Mass inNormotensive, Normal-Weight Individuals LV indicates left ventricular * P < 0001vs men. Gender-Specific Differences in Cardiac Function

21. Gender Differences in Mitochondrial Function Male Female 6000 4000 2000 0 pmol O 2 * s -1 * g tissue -1 * Justo et al., Am J Physiol 289: C372-378, 2005 Male Female

22. Vina et al. 2005, FEBS Letters 579: 2541-2545 Gender Differences in Oxidative Defense Mechanisms

23. Gender Differences in ROS Generation at Physical Exercise Esbjörnsson-Liljedahl et al. J Appl Physiol 93: 1075-1083, 2002 30 s cycle sprint 20 min rest

24. Estrogen modified from Brandes et al. Cardiovasc Res (2005) 66: 286-294 + Akt, NO Cherif et al. (2003) Nucleic Acids Research 31: 1576-1583 Gender Differences in Telomere Lengthening

25. Gender Differences in Oxidative Stress and Cardiac Aging - Prevention and Therapeutical Consequences: Conclusions and Perspectives Hormonal Replacement Therapy Nutritional Supplementation (e.g. phytoestrogenes?, gender-specific nutrion recommendations...)

26. Oxidative Stress and Physical Exercise ‚Cologne Marathon‘ 0 100 200 300 400 500 600 700 1234567891011121314151617181920212223 before after Reactive Oxygen Metabolites Laatsch, Türk, Predel Brixius, Bloch et al. 2006 unpublished results + Antioxidants Arbitrary Units

27. Gender Differences in Oxidative Stress and Cardiac Aging - Prevention and Therapeutical Consequences: Conclusions and Perspectives Hormonal Replacement Therapy Nutritional Supplementation (e.g. phytoestrogenes?, gender-specific nutrion recommendations...) Physical exercise in young and old persons

28. The Cologne Cardiac Anti-Aging Program

29. Kölle Alaaf !