Is Lipid Peroxidation of Polyunsaturated Acids the Only Source of Free Radicals That Induce Aging and Age-related Diseases?

The increase in free radicals is hypothesised to cause aging and age-related diseases. The most common source of free radicals is thought to be superoxide. This superoxide is claimed to be released from mitochondria during the enzymatic transformation of oxygen to water by a "leakage" process. This article presents evidence that leakage does not occur. Instead, protonated superoxide radicals are generated by lipid peroxidation processes. In nature, polyunsaturated fatty acids (PUFAs) represent particularly oxygen-sensitive compounds. Apparently, nature uses this sensitivity for signalling processes by producing lipidhydroperoxides (LOOHs) by any change to cell membrane structure. LOOHs easily undergo further enzymatic transformations to compounds which contribute to activation of genes. Bivalent metal ions within the active site of lipoxygenases catalyse LOOH production. The metal ions generate radicals which are transformed within the enzyme complex to non-radical molecules. Thus radicals never leave the enzyme complex except in severe stress situations. In this case the radical intermediates attack bonds, keeping the metal ion in its complex state. Thus, metal ions are released and react in a Fenton reaction with LOOH molecules produced earlier by lipoxygenase to form LO. radicals. Radicals are typically four orders of magnitude more reactive than non-radical molecules. Their action is not under genetic control, they attack nearly all biological molecules, destroying lipids, proteins, nucleic acids, hormones and enzymes until the radicals are quenched by scavenger molecules. The principal degradation routes are outlined in this review. Lysophospholipids are generated in large amounts after stress by activation of phospholipases and are transformed to LO. radicals. These can abstract a hydrogen radical from a lysophospholipid. The radical thus formed adds oxygen and decomposes to a 2-oxolysophospholipid and a HOO. radical (protonated superoxide). HOO. radicals in turn abstract hydrogen atoms from other molecules and produce H(2)O(2). Since any cell preparation method causes membrane destruction, it is inevitable that protonated superoxide is generated, explaining why H(2)O(2) molecules are found as "byproducts" of many reactions.