Aging and Lysosomal Degradation of Cellular Constituents

Abstract

Biological structures are continuously renewed through degradation and resynthesis of their worn-out/damaged constituents. Cells possess a number of mechanisms to degrade their components. Many cytosolic proteins, mainly short-lived ones, are decomposed by calcium-dependent cysteine proteases, calpains [1], as well as by multicatalytic proteinase complexes, proteasomes [2]. Most long-lived proteins, lipids, other biomolecules, and all organelles are, however, degraded by lysosomes, acidic vacuolar organelles containing several dozens lytic enzymes [3, 4]. Initially, the material to be degraded is sequestered and wrapped up in an autophagosome, a vacuolar structure surrounded by a specific membrane. Autophagosomes then fuse with lysosomes [5, 6]. This process is called macroautophagy. Besides, the material can enter lysosomes through invagination of the membrane (microautophagy) [7] or by selective chaperone-mediated autophagy [6]. Within lysosomes, the material is decomposed into simple molecules, such as amino acids, fatty acids and monosaccharides, which are carried into the cytosol and reutilized in anabolic activities. A failure to synthesize even a single lysosomal enzyme results in serious, often fatal, disorders, known as lysosomal storage diseases [8, 9]. Normally, lysosomes efficiently degrade most autophagocytosed macromolecules and organelles, providing for their successful recycling. The role of lysosomes, along with other recycling systems, is particularly important for postmitotic cells, which cannot renew themselves by cell division. In contrast, proliferating cells, such as intestinal epitheliocytes or bone marrow cells, continuously dilute their worn-out/damaged constituents during successive divisions, normally associated with intense de novo formation of macromolecules and organelles [10].