Proteasome activity declines in aged macrophages

Abstract

The ubiquitin-proteasome pathway is involved in regulation of a variety of biologically important processes including antigen presentation by macrophages (Mφ). Age-related decrease in proteasome activity has been reported in other tissues. However, the effect of aging on the ubiquitin-proteasome pathway in Mφ has not been systematically studied. Thioglycollate-elicited Mφ from young (4–6 mo) and Old (24–26 mo) male C57BL/6NIA mice were collected by lavage. Mφ from old mice exhibited significantly lower activity of all three proteasome peptidases [chymotrypsin-like activity (young vs old, Mean ± SE): 100 ± 13 vs 62 ± 4, p<0.05; trypsin-like activity: 100 ± 4 vs 56 ± 3, p<0.01; acidic activity: 100 ± 7 vs 58 ± 6, p<0.01]. The age-related decrease in proteasome activity was not due to decreased expression of proteasome subunits, since levels of C2 and S1 subunits were higher in old Mφ than young (C2: 100 ± 20 vs 167 ± 13, p<0.05; S1: 100 ± 15 vs 183 ± 20, p<0.01) while there was no significant age-related difference in levels of α5, LMP2 and LMP7. The decrease in proteasome activity was associated with an increase in the levels of ubiquitin conjugates. Furthermore, the levels of 2 ubiquitination-related enzymes, E1 and E2 (Ubc7), were significantly higher in old Mφ than young. The age-related decline in proteasome activity and the paralleled increase in levels of ubiquitin conjugates indicate that the function of the ubiquitin-proteasome pathway is impaired in the aged Mφ. The decrease in proteasome activity in Mφ might contribute to the age-related decline in the ability of Mφ to present antigens to T cells, a proteasome dependent process. Supported by USDA #58-1950-9-001 and NIA #R01 AG009140-10A1.