Oxidative stress, accumulation of biological 'garbage', and aging.
Normal metabolism is associated with unavoidable mild oxidative stress resulting in biomolecular damage that cannot be totally repaired or removed by cellular degradative systems, including lysosomes, proteasomes, and cytosolic and mitochondrial proteases. Consequently, irreversibly damaged and functionally defective structures (biological 'garbage') accumulate within long-lived postmitotic cells, such as cardiac myocytes and neurons, leading to progressive loss of adaptability and increased probability of death and characterizing a process called aging, or senescence. Intralysosomal 'garbage' is represented by lipofuscin (age pigment), an undegradable autophagocytosed material, while extralysosomal 'garbage' involves oxidatively modified cytosolic proteins, altered biomembranes, defective mitochondria and other organelles. In aged postmitotic cells, heavily lipofuscin-loaded lysosomes perform poorly, resulting in the enhanced accumulation of defective mitochondria, which in turn produce more reactive oxygen species causing additional damage (the mitochondrial-lysosomal axis theory). Potential anti-aging strategies may involve not only overall reduction of oxidative stress, but also the use of intralysosomal iron chelators hampering Fenton-type chemistry as well as the stimulation of cellular degradative systems.
Terman
Alexei
A
Division of Experimental Pathology, Faculty of Health Sciences, Linköping University, Linköping, Sweden. alete@inr.liu.se
Brunk
Ulf T
UT
D000375:Aging / Q000502:physiology*; D000818:Animals; D003643:Death; D006801:Humans; D008062:Lipofuscin / Q000502:physiology; D008247:Lysosomes / Q000502:physiology; D008938:Mitosis; D008954:Models, Biological; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species
D008062:Lipofuscin; D017382:Reactive Oxygen Species