LECTURE-7 - Simplified Signaling Pathways of Apoptosis...

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LECTURE 7 Apoptosis in Aging, Disease and Exercise Christiaan Leeuwenburgh, Ph.D. Biochemistry of Aging Laboratory, University of Florida, Gainesville, FL 32611 Simplified Signaling Pathways of Apoptosis Pollack M, Leeuwenburgh C: Apoptosis and Aging; Role of the Mitochondria, J Gerontol A Biol Sci Med Sci 2001; 56: B475-482. Chronic Oxidative Stress and Apoptosis Myocardial Aging, Sarcopenia, Neurodegeneration È in total number of skeletal and heart myocytes as well as neurons with age •May lead to accelerated decline in cardiac functional capacity, sarcopenia, neurodegenerative diseases •Oxidative Stress and Apoptosis may be one major factor Mitochondria and Apoptosis • Aging progressive deterioration in physiological functions and metabolic processes, i.e., Mitochondrial Dysfunction • Radical-mediated mitochondrial damage accumulates over time and may account for age-related induction of apoptosis. Mitochondrial/Free Radical Theory of Aging Oxidative stress mt-DNA damage mt-DNA deletions Oxidized proteins Lipid peroxidation Lipid-adduct formation Decrease in repair systems Leeuwenburgh, C., Wagner, P., Holloszy, J.O., Sohal, R.S., and Heinecke, J.W. 1997. . Arch Biochem Biophys 346:74-80. Drew, B., Phaneuf, S., Dirks, A., Selman, C., Gredilla, R., Lezza, A., Barja, G., and Leeuwenburgh, C. (2003). Am J Physiol Regul Integr Comp Physiol 284, R474-R480. ACUTE ACTIVATION OF MITOCHONDRIAL MEDIATED APOPTOSIS Control Doxorubicin 0 100 200 300 * A Cytochrome c (ng/mg protein) Control Doxorubicin 0 B * Caspase-3 Activity (pmol/min/mg protein) Control Doxorubicin 0 10 20 30 * C Apoptotic Index (Arbitrary OD/mg protein) Green, P., and Leeuwenburgh, C. (2002) Mitochondrial dysfunction is an early indicator of doxorubicin-induced apoptosis. Biochim Biophys Acta 1588, 94 Childs, A. C., Phaneuf, S. L., Dirks, A. J., Phillips, T., and Leeuwenburgh, C. (2002) Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Res 62, 4592-4598 0 10 20 30 40 50 60 0 10 20 30 40 Control Doxorubicin * * * * Time (Min) Absorbance at 550 nm
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In disease conditions there is strong evidence that apoptosis occurs and is partly mitochondrial-mediated. Is there evidence in normal Aging? Myocardial Aging and Apoptosis È in total # of myocytes with age • May lead to accelerated decline in cardiac functional capacity • Apoptosis may be one major factor Necrotic and apoptotic myocyte cell death in the aging heart of F344 rats (Kajstura et al., Am. J. Phys., 1996) 3 7 12 16 24 3 7 12 16 24 0 250 500 750 1000 * ** Age (Months) Number of Apoptotic Nuclei/Ventricle 3 7 12 16 24 0 5 10 15 * ** Age (Months) Necrotic Myocytes 10 3 ** ** ** Necrotic and apoptotic myocyte cell death in the aging heart of Fischer 344 rats (Kajstura et al., Am. J. Phys., 1996) • Apoptosis and necrosis Ç with age in hearts of male F344 rats • Apoptosis = 140 Cells at 3 months vs.
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This note was uploaded on 05/19/2011 for the course BCH 3218 taught by Professor Johnsteward during the Fall '08 term at University of Florida.

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LECTURE-7 - Simplified Signaling Pathways of Apoptosis...

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