The Effects of Aging on Proteasome Activity, Assembly, and Abundance in C. elegans

Abstract: Aging is associated with the accumulation of misfolded and damaged proteins. This accumulation is the result of an imbalance of proper protein folding, maintenance, and disposal. Maintaining proteostasis is critical to the health and life of an organism. While studies consistently observe that the proteostasis network diminishes with age, the effects on individual mechanisms have not been determined. Of interest is the effect of aging on protein degradation. Proteasomal degradation is a primary path of protein degradation in all eukaryotes. Though many studies have investigated proteasome activity with age, results vary depending on the organism, tissue, and specific activity of the proteasome tested. It seems as though alterations in proteasome activity can either instigate, or potentially compensate for, a diminished proteostasis network. In order to better understand the effects of proteostasis decline on aging and disease, it is important to determine the role of the proteasome. As in most organisms, C. elegans show an age-related accumulation and aggregation of proteins. This suggests a failure to properly dispose of proteins, potentially by diminished proteasome activity. Surprisingly, we observe a significant increase in proteasome activity with age in the adult worm. The activity increase is apparent in the chymotrypsin-like, trypsin-like, and caspase-like activities. Lifespan extending methods have been shown to ameliorate age related toxic protein accumulation in the worm and have hallmarks of improved proteostasis. Interestingly, we observe a decrease in relative proteasome activity in long lived worms. In aging C. elegans, we determine that proteasome activity increases with age to compensate for the decline in general proteostasis. This increased activity is regulated by increasing proteasome abundance, likely through the regulation of limiting subunits