KRONOS - Dityrosine: A Non-invasive Biomarker to Monitor...

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1 Dityrosine: A Non-invasive Biomarker to Monitor Aging? Christiaan Leeuwenburgh, Ph.D. Biochemistry of Aging Laboratory College of Health and Human Performance Department of Exercise and Sport Sciences Center for Exercise Science, College of Medicine Prepared for: The Kronos sm Science Laboratory Studies in The Biochemistry of Aging Laboratory 1. Mitochondrial Oxidative Stress and Aging 2. Mitochondrial-induced Apoptosis and Aging 3. Toxicity of Doxorubicin on the Heart Human Studies on Aging, Nutrition, Exercise/Inflammation Inflammation in healthy humans Nutritional interventions Finding non-invasive markers of oxidative stress to monitor aging and disease states in humans Clinical Research Analytical Chemistry Molecular Biology-Biochemistry Neeharika, Choudry , M.D. Barry Drew, Ph.D. Rajani Shelke, Ph.D. Tracey Philips* Mina Hiona* Sharon Phaneuf* * Ph.D. students AmieDirks*
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2 Outline Animal Studies Aging, Caloric Restriction and Dityrosine Antioxidant Therapy and Dityrosine Human Studies Kwashiorkor and Dityrosine Pilot data on Aging Humans and Urinary levels of Dityrosine Now also found in the inter-membrane space of mitochondria Citrate Synthase HO• NO 2 •+ HO• ONOO - Tyr •
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3 Leeuwenburgh et al 1997. J Biol Chem . 272:3520 -6. Leeuwenburgh et al 1997. J Biol Chem . 272:1433 -6. 0 1 2 3 0 1 2 Hydrogen Peroxide (2 mM) + Copper (0.1 mM) Hydroxyl Radicals Hours o-Tyrosine/Phenylalanine (mmol/mol) 0 5 15 30 60 0 2 4 Tyrosyl Radical Myeloperoxidase (HRP;100nM) Hydrogen Peroxide (200 μ M) Tyrosine (2 mM) Minutes Dityrosine/Tyrosine 0 30 100 300 0 10 20 Reactive Nitrogen Species Peroxynitrite [ m M] 3-Nitrotyrosine/Tyrosine Quantification of Oxidized Amino acids by Gas Chromatography - Mass Spectrometry • Acid Stable 13 C Labeled Internal Standards • HCl-Propanol / Heptafluorobutyric Anhydride. • Negative Chemical Ionization (Methane) • DB-1 capillary column 12 meter • Selected Ion Monitoring • Quantification: Ratio of Authentic and Corresponding Labeled Standard
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4 In vitro Gas Chromatography Mass Spectrometry is used to detect oxidative stress “fingerprints” Hydroxyl radicals, tyrosyl radicals, and reactive nitrogen increase levels of o- tyrosine, o,o’- dityrosine, and 3- nitrotyrosine in vitro Aging, oxidant production, antioxidant defenses and detection of oxidative damage What is the oxidants production in a day? • Using 3.5ml O
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KRONOS - Dityrosine: A Non-invasive Biomarker to Monitor...

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