Decreased proteasome-mediated degradation in T cells from the elderly: A role in immune senescence

Induction of NF kappa B is a highly regulated process requiring phosphorylation, ubiquitination, and proteasome-mediated degradation of the cytosolic inhibitor I kappa B alpha. Analyses of the regulation of I kappa B alpha in TNF-alpha-treated T lymphocytes from young and elderly donors revealed severely compromised degradation of I kappa B alpha in T cells from the elderly, Examination of activation-induced phosphorylation and ubiquitination of I kappa B alpha 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 I kappa B alpha in the elderly. This failure to degrade I kappa B alpha may underlie both the observed decrease in NF kappa B 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. (C) 1999 Academic Press.