Catabolic insufficiency and aging.
Cellular degradative processes, which include lysosomal (autophagic) and proteasomal degradation, as well as the activity of cytosolic and mitochondrial proteases, provide for a continuous turnover of damaged and obsolete biomolecules and organelles. Inherent insufficiency of these degradative processes results in progressive accumulation within long-lived postmitotic cells of biological "garbage" ("waste" material), such as indigestible protein aggregates, defective mitochondria, and lipofuscin (age pigment), an intralysosomal, polymeric, undegradable material. Intracellular "garbage" is neither completely catabolized, nor exocytosed to any considerable extent. Heavy lipofuscin loading of lysosomes, typical of old age, seems to pronouncedly decrease autophagic potential. As postulated in the mitochondrial-lysosomal axis theory of aging, this occurs on account of the transport of newly synthesized lysosomal enzymes to lipofuscin-loaded lysosomes rather than to active lysosomes/late endosomes, making the enzyme content of autophagolysosomes insufficient for proper degradation. Consequently, the turnover of mitochondria progressively declines, resulting in decreased ATP synthesis and enhanced formation of reactive oxygen species, inducing further mitochondrial damage and additional lipofuscin formation. With advancing age, lipofuscin-loaded lysosomes and defective mitochondria occupy increasingly larger parts of long-lived postmitotic cells, leaving less and less capability for normal turnover and ATP production, finally resulting in cell death.
Terman
Alexei
A
Division of Experimental Pathology, Linköping University, Sweden. alete@inr.liu.se
D000375:Aging / Q000502:physiology; D000818:Animals; D001343:Autophagy / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology*; D006801:Humans; D008062:Lipofuscin / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D008660:Metabolism; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress / Q000502:physiology
D008062:Lipofuscin