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Age-Related Changes in Protein Oxidation and Proteolysis in Mammalian Cells

^a Clinics of Physical Medicine and Rehabilitation, Medical Faculty (Charité), Berlin, Germany
^b Ethel Percy Andrus Gerontology Center, Division of Molecular Biology, the University of Southern California, Los Angeles

Kelvin Davies, Ethel Percy Andrus Gerontology Center, University of Southern California, 3715 McClintock Avenue, Room 306, Los Angeles, CA 90089-0191 E-mail: kelvin{at}usc.edu.

Decision Editor: John Faulkner, PhD

Reactive oxygen species generated as by-products of oxidative metabolism, or from environmental sources, frequently damage cellular macromolecules. Proteins are recognized as major targets of oxidative modification, and the accumulation of oxidized proteins is a characteristic feature of aging cells. An increase in the amount of oxidized proteins has been reported in many experimental aging models, as measured by the level of intracellular protein carbonyls or dityrosine, or by the accumulation of protein-containing pigments such as lipofuscin and ceroid bodies. In younger individuals, moderately oxidized soluble cell proteins appear to be selectively recognized and rapidly degraded by the proteasome. An age-related accumulation of oxidized proteins could, therefore, be a result of declining activity of the proteasome. Previous research to investigate the notion of an age-related decline in the content and/or activity of the proteasome has generated contradictory results. The latest evidence, including our own recent findings, indicates that proteasome activity does, indeed, decline during aging as the enzyme complex is progressively inhibited by oxidized and cross-linked protein aggregates. We propose that cellular aging involves both an increase in (mitochondrial) oxidant production and a progressive decline in proteasome activity. Eventually so much proteasome is inactivated that oxidized proteins begin to accumulate rapidly and contribute to cellular dysfunction and senescence.

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