Protein turnover by the proteasome in aging and disease.
A significant body of evidence supports a key role for free radicals in causing cumulative damage to cellular macromolecules, thereby contributing to senescence/aging, and a number of age-related disorders. Proteins are recognized as major targets for oxidative damage (in addition to DNA and lipids) and the accumulation of oxidized proteins has been reported for many experimental aging models, as measured by several markers for protein oxidation. In young and healthy individuals, moderately oxidized soluble cell proteins are selectively and rapidly degraded by the proteasome. However, severely oxidized, cross-linked proteins are poor substrates for degradation and actually inhibit the proteasome. Considerable evidence now indicates that proteasome activity declines during aging, as the protease is progressively inhibited by binding to ever increasing levels of oxidized and cross-linked protein aggregates. Cellular aging probably involves both an increase in the generation of reactive oxygen species and a progressive decline in proteasome activity, resulting in the progressive accumulation of oxidatively damaged protein aggregates that eventually contribute to cellular dysfunction and senescence.
Shringarpure
Reshma
R
Ethel Percy Andrus Gerontology Center and the Division of Molecular & Computational Biology, the University of Southern California, Los Angeles, CA 90089-0191, USA.
Davies
Kelvin J A
KJ
D000375:Aging / Q000378:metabolism*; D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D004194:Disease; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
D005609:Free Radicals; D009097:Multienzyme Complexes; D011506:Proteins; D017382:Reactive Oxygen Species; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex