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Oxidants and Aging

Oxidants and Aging. Rolf J. Mehlhorn Lawrence Berkeley Laboratory. Free Radicals. Free radicals are unstable React quickly with other compounds, doing cell and body damage Once produced, they multiply unless neutralized by anti-oxidants or other free-radical scavengers.

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Oxidants and Aging

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  1. Oxidants and Aging Rolf J. Mehlhorn Lawrence Berkeley Laboratory

  2. Free Radicals • Free radicals are unstable • React quickly with other compounds, doing cell and body damage • Once produced, they multiply unless neutralized by anti-oxidants or other free-radical scavengers.

  3. The Free Radical Theory of Aging “Aging results from the deleterious effects of free radicals produced in the course of cellular metabolism” Harman D., Aging: A theory based on free radical and radiation chemistry, J. Gerontol. 11: 298, 1956

  4. What is a free radical? • It is a molecule having unpaired electrons • Therefore, free radicals are unstable • A single molecule can have several unpaired electrons, notably oxygen which can be thought of as a bi-radical • ROS = Reactive Oxygen Species • Free radicals rarely occur in nature • Magnetic properties allow for detection

  5. Free Radical Chemistry • Reactive radicals attack indiscriminately • Can add to unsaturated bonds • Can abstract electrons or hydrogen atoms • Propagate chain reactions • Can cause bond scission • Can cause crosslinking • Crosslinking - Formation of bonds among polymeric chains • Produce secondary toxic agents

  6. Implications for Aging • Some free radical-induced chemical modifications may have unique impacts • Crosslinked products may not be degradable • Scission of bonds in DNA, particularly multiple events may erase vital information

  7. Oxygen Toxicity • At high pressure oxygen is always lethal • Convulsions precede death -- the onset time is a direct function of the oxygen pressure • Animals have a limited capacity to adapt to oxygen toxicity • Microbes from anaerobic environments are killed by traces of oxygen

  8. How can oxygen be toxic? • It is chemically much more reactive than most other small molecules • It can be activated by sequential one-electron reductions to superoxide, hydrogen peroxide or hydroxyl radical (ROS) • It can be converted to reactive singlet oxygen • For example: Reactive oxygen molecule produced by respiratory burst in immune cells, phagocytes, are toxic to microbial cells

  9. Immune System Oxidants Activated T-Cell Antigen

  10. What are the Major Oxidants? • Hydroxyl radical (OH.) • Hypochlorite (HOCl) • Singlet oxygen 1O2 • Peroxynitrite (OONO-) • Hydrogen peroxide (H2O2) • Free or loosely-bound iron, copper or heme • Superoxide radical (O2.-) • Nitric oxide (NO.)

  11. Lipid Peroxidation • PUFAs* contain weakly bonded hydrogen atoms between double bonds • Chain reactions are probable because of high local concentrations of double bonds *PUFAs means polyunsaturated fatty acids

  12. Enzymes involved in cell signaling Immune cells “Leaky” electron transport Damaged proteins and lipids Toxins (food, water) Smoke Irradiation (UV) Oxidant SourcesTable 5.1 Regulated Unregulated

  13. Major AntioxidantsTable 5.2 • Vitamins E and C • Thiols, particularly glutathione • Uric acid • Superoxide dismutases (Cu/Zn or Mn SOD) • Catalase and glutathione peroxidase • Heme oxygenases • Protein surface groups (Msr)

  14. Antioxidants • Vitamin E • Vitamin C

  15. Free Radical Damage Markers • Fluorescent age pigments • DNA products like hydroxylated bases • Protein products like carbonyls & bityrosine • Lipid products like isoprostanes

  16. Mitochondria • Have been regarded as the “pacemakers of aging” by some investigators • Superoxide is released as a direct function of the energy state (high ATP/ADP, strongly reducing conditions) • Uncoupling proteins dissipate excess energy as heat, are induced by superoxide; some require free fatty acids for activity

  17. Glucose and Oxidants • In cell culture models high glucose correlates with oxidant production • Three diabetes-linked effects can be correlated with superoxide production • Insulin pathway and life-span extension

  18. Are Oxidants the Cause of Aging? (Table 5.8)

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