Aging: central role for autophagy and the lysosomal degradative system.

The lysosomal network is the major intracellular proteolytic system accounting for more than 98% of long-lived bulk protein degradation and recycling particularly in tissues such as liver and muscles. Lysosomes are the final destination of intracellular damaged structures, identified and sequestered by the processes of macroautophagy and chaperone-mediated autophagy (CMA). In the process of macroautophagy, long-lived proteins and other macromolecular aggregates and damaged intracellular organelles are first engulfed by autophagosomes. Autophagosomes themselves have limited degrading capacity and rely on fusion with lysosomes. Unlike macroautophagy, CMA does not require intermediate vesicle formation and the cytosolic proteins recognized by this pathway are directly translocated to the lysosomal membrane. Aging is a universal phenomenon characterized by progressive deterioration of cells and organs due to accumulation of macromolecular and organelle damage. The continuous removal of worn-out components and replacement with newly synthesized ones ensures cellular homeostasis and delays the aging process. Growing evidence indicate that the rate of autophagosome formation and maturation and the efficiency of autophagosome/lysosome fusion decline with age. In addition, a progressive increase in intralysosomal concentration of free radicals and the age pigment lipofuscin further diminish the efficiency of lysosomal protein degradation. Therefore, integrity of the autophagosomal-lysosomal network appears to be critical in the progression of aging. Discovery of the genes involved in the process of autophagy has provided insight into the various molecular pathways that may be involved in aging and senescence. In this review, we discuss the cellular and molecular mechanisms involved in autophagy and the role of autophagosome/lysosome network in the aging process.