Age-related changes in protein oxidation and proteolysis in mammalian cells

Reactive oxygen species generated as by-products of oxidative metabolism, o r from environmental sources, frequently damage cellular macromolecules. Pr oteins are recognized as major targets of oxidative modification, and the a ccumulation 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 protei n carbonyls or dityrosine, or by the accumulation of protein-containing pig ments such as lipofuscin and ceroid bodies. In younger individuals, moderat ely 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 protea some. Previous research to investigate the notion of an age-related decline in the content and/or activity of the proteasome has generated contradicto ry results. The latest evidence, including our own recent findings, indicat es that proteasome activity does, indeed, decline during aging as the enzym e complex is progressively inhibited by oxidized and cross-linked protein a ggregates. We propose that cellular aging involves both an increase in (mit ochondrial) oxidant production and a progressive decline in proteasome acti vity. Eventually so much proteasome is inactivated that oxidized proteins b egin to accumulate rapidly and contribute to cellular dysfunction and senes cence.