Decreased Proteasome-Mediated Degradation in T Cells from the Elderly: A Role in Immune Senescence

Induction of NFκB is a highly regulated process requiring phosphorylation, ubiquitination, and proteasome-mediated degradation of the cytosolic inhibitor IκBα. Analyses of the regulation of IκBα in TNF-α-treated T lymphocytes from young and elderly donors revealed severely compromised degradation of IκBα in T cells from the elderly. Examination of activation-induced phosphorylation and ubiquitination of IκBα did not demonstrate any significant age-related alterations. However, examination of proteasome activity in these T cells using fluorogenic peptide assays revealed a significant age-related decline in chymotryptic activity. These results suggest that a decline in proteasome activity results in a failure to fully degrade IκBα in the elderly. This failure to degrade IκBα may underlie both the observed decrease in NFκB induction and the IL-2 receptor expression in TNF-treated T cells during aging. Thus, decreased proteasome-mediated degradation may be central to immune dysfunction that accompanies aging.