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

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

Cardiac Stress Oxidative Stress

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

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

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

Oxidative Enzymes : NAD(P)H-Oxidases

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

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

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

Oxidative Stress : Definition Antioxidative Defense ROS

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)

* n=6 n=6 n=9 n=9 8-Isoprostan Strassburger et al. Free Radical Biology & Medicine (2005) 38: 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

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

Differential Down-Regulation of Peroxiredoxin Isoforms in Human Failing Myocardium Peroxiredoxin 1Peroxiredoxin 2Peroxiredoxin 3 Peroxiredoxin 4Peroxiredoxin 5 Peroxiredoxin 6 NFDCM NFDCM DU/µg prot. NF n=6 DCM NFDCM DU/µg prot. NFDCM p= DU/µg prot. p=0.06 NFDCMNFDCM p=0.07 DU/µg prot. NFDCM NFDCM NFDCM DU/µg prot. p=0.06 NFDCM NFDCM Number of experiments,NF and DCM: n=6 each Brixius, Bloch, 2006, in preparation

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

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

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

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

Stroke Work/LV Mass, g-m/beat per gram Stroke Work Index/LV Mass, g-m/beat/m 2 per gram 0.89 ± ± 0.1 * Men (n = 229) Women (n = 164) 0.97 ± ± 0.15 * De Simone et al., Hypertension 31: , 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

Gender Differences in Mitochondrial Function Male Female pmol O 2 * s -1 * g tissue -1 * Justo et al., Am J Physiol 289: C , 2005 Male Female

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

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

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

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...)

Oxidative Stress and Physical Exercise ‚Cologne Marathon‘ before after Reactive Oxygen Metabolites Laatsch, Türk, Predel Brixius, Bloch et al unpublished results + Antioxidants Arbitrary Units

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

The Cologne Cardiac Anti-Aging Program

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