Usha Ponnappan

Department of Geriatrics, Medicine, Microbiology and Immunology, University of Arkansas for Medical Sciences, and GRECC, John L. McClellan Memorial VA hospital, VA Medical Research, GC143, 151/LR, 4300 West 7^th street, Little Rock, Arkansas 72205

Received 1/15/97 Accepted 1/29/98

6. CONCLUSIONS AND PERSPECTIVES

Altered 26S proteasomal activity in T lymphocytes appears to contribute to age-related T cell dysfunction by inhibiting the induction of NF kappa B. This occurs via a mechanism in which decreased activity of the proteasome impairs the degradation of I kappa B-alpha which in turn results in lowered NF kappa B induction. Thus, altered activity of the proteasome correlates with altered NF kappa B induction. These results would predict that the degradation of other cellular proteins dependent on the chymotryptic activity of the proteasome would also be impaired during aging, including the precursors of NF kappa B, p105 and p100. Proteins such as the cell cycle inhibitor p27 kip and other cell cycle regulators such as cyclins A and B whose proteasome mediated degradation is important for cell cycle progression would be affected during aging (189,190). Thus, decreased proteasomal activity may explain the age-related decline in T cell proliferation not only through the decreased induction of NF kappa B but also via impaired degradation of cell cycle regulators.

Decreased proteasomal activity in T cells from elderly individuals is a novel finding and has far reaching implications as the proteasome has now been recognized to play important roles in many cellular processes including antigen presentation, cell cycle regulation, and apoptosis (153,190-192). Therefore, decreased activity of the proteasome in the elderly may not only mediate lowered NF kappa B induction but dysregulation of other processes important in cellular function. Altered proteasome activity may affect the processing of self or viral peptides for presentation by MHC I thereby affecting immune responses. Whether, the decline in proteasomal activity is exclusive to any given subset of T cells or other cells of the immune system remains to be investigated. Earlier studies using in vitro cellular senescence models have demonstrated no age associated change in the 20S proteasome activity. Whether the decrease noted in T cells is exclusive to the immune system, needs further investigation.

Recently, proteasomal activity has been shown to be involved in apoptosis (191,192). An alteration therefore in the activity of the proteasome may interfere with the apoptosis of T cells during immune responses thus affecting homeostatic regulation of an ongoing immune response. The decrease in proteasomal activity with age in the T cell compartment needs rigorous future experimentation. As the proteasome plays a central role in the processes of the T cell, a defect in the proteasomal activity is likely to impact on several facets of cellular function ranging from simple protein turnover to complex events of mitosis. The accumulation of aberrant proteins and multi-ubiquitinated proteins during aging may be hypothesized to be due to a central defect in the proteasomal degradation.