Protein degradation by the proteasome and its implications in aging.

Free radical damage to cellular components is believed to contribute to the aging process. Studies on proteins have shown both an age-related decline in several enzyme activities and an age-related accumulation of oxidized forms of protein. Oxidized forms of protein are generally degraded more rapidly than their native counterparts. Indeed, the normal functions of the cell involve the regular elimination of these altered molecules. The proteasome, a multienzymatic proteolytic complex, is the major enzymatic system in charge of cellular "cleansing" and plays a key role in the degradation of damaged proteins. Consequently, proteasome function is very important in controlling the level of altered proteins in eukaryotic cells. Because the steady-state level of oxidized protein reflects the balance between the rate of protein oxidation and the rate of protein degradation, age-related accumulation of altered protein can be due to an increase of free radical-mediated damage, a loss of protease activity, or the combination of both mechanisms. One of the hypotheses put forward to explain the accumulation of altered proteins is the decrease of proteasome activity with age. In this paper, the importance of oxidative damage to proteins and that of their elimination by the proteasome are first described. Then, evidence for a decline of proteasome activity upon aging and upon oxidative stress is provided by studies from our and other laboratories.