Lipofuscin and ceroid formation: the cellular recycling system.

Lipofuscin, age pigment, is a dark pigment with a strong autofluorescence seen with increasing frequency with advancing age in the cytoplasm of postmitotic cells. By bright-field light microscopy lipofuscin appears as irregular yellow to brown granules ranging in size from 1-2 nm in diameter. The fluorescent spectra of lipofuscin in situ generally show excitation maxima at about 360 nm and a yellowish emission maxima at 540-650 nm. Ultrastructurally the granules, localized in residual body-type lysosomes, are extremely heterogeneous and vary from one cell type to another, and frequently within a single cell. The pigment granules usually contain numerous liquid droplets embedded in an electron-dense matrix. The granules stain positively for neutral lipids but are not soluble in polar or non-polar lipid solvents. Lipofuscin contains about 50 percent by weight of proteinaceous substances, a lesser fraction of lipid-like material, and probably less than one percent by weight fluorophore(s); it is enriched in metals such as Al, Cu, and Fe, and in dolichols. Free radical reactions and the proteolytic system are implicated in lipopigment formation. Thus the rate of lipopigment formation is increased by vitamin E deficiency and by increased intake of polyunsaturated fatty acids as well as by protease inhibitors such as leupeptin. Free radical reactions and proteolysis are involved in the continual turnover of cellular components. Cellular damage from free radical reactions, and others such as hydrolysis, has been present since the beginning of life. The evolution of more complex cells necessitated development of defenses - DNA repair processes, antioxidants, etc. - against damaging reactions as well as the removal and replacement of altered parts, and of those no longer needed by the cells. Proteins "marked" for disposal by oxidation damage, or other means such as conjugation with ubiquitin, are apparently rendered more hydrophobic so that they are "recognized" for degradation by the lysosomes and the proteinases and peptidases of the cytosol and mitochondria. Oxidatively altered lipids are removed by enzymes such as phospholipase A2. The products of the degradation processes are reused by the cells. Normally the recycling of damaged components works extremely well. There may be some slow slippage with advancing age as the rate of free radical damage increases while protease activity decreases. As a result a gradually increasing fraction of lysosomal "food" may be converted to non-digestible forms, lipofuscin, before it can be broken down to reusable components. Ceroid is apparently formed when the disposal system is "overloaded" or impaired.(ABSTRACT TRUNCATED AT 400 WORDS)