The ubiquitin proteasome pathway (UPP) modulates a variety of cellular processes ranging from antigen processing to cell cycle progression, including the regulation of transcription factor, NFkB, within the immune system. Decreased UPP has now been associated with age-related degenerative diseases. We have identified specific impairment of proteolytic activity of the proteasome during aging, in both the memory and naove subsets of human T lymphocytes. Further, we have demonstrated this impairment in activity to underlie activation-induced defects in the generation of transcription factor NFkB, ultimately resulting in lowered IL-2R expression and IL-2 secretion. Preliminary data presented here demonstrate, that in addition to a decline in specific subunits of the proteasome per se, there is a significant decrease in the levels of heat shock protein-90 (HSP-90) associated with the 26S proteasome in T cells from the elderly. Thus, if a decrease in the levels proteasomal subunits and associated proteins accounts for some of the decline in activity that contribute to immune dysfunction during aging, then induction of proteasome subunits and accessory proteins in, principal, should retard these changes and thus induce catalytic activity leading to improved immune function.Therefore, this application is designed to evaluate the physiological benefit of induced UPP expression on immune function in the elderly. Our working hypothesis is that induction and/or upregulation of ubiquitin-proteasome function may serve as a novel method to ameliorate immune senescence. We will test this hypothesis through the following specific aims : (1) Determine the underlying mechanism of proteasomal impairment in T cell subsets from the elderly by focussing on the role of proteasomal subunits and HSP-90, (2) Delineate the functional effects of enhanced UPP induction on T cell responses such as induction of NFkB, IL-2R expression, IL-2 secretion, and proliferation, to delineate its contribution to improving immune function during aging, (3) Study the pharmacokinetics and pharmacodynamics of UPP inducers in aged mice focussing on lymphocytes as targets and (4) Study the role of UPP inducers on enhancing immune response to vaccination in influenza challenged aged mice, as an in vivo correlate of the modulation observed in human primary T cells during aging.
This application aims to understand the molecular and biochemical basis of lowered responses to vaccination and increased susceptibility to infection in the elderly. Previous work from our laboratory has demonstrated that proteins that act as chaperones and proteins that are responsible for garbage disposal in the immune system are defective. These defects appear to underlie decrease in resistance that often accompanies aging in humans. We are now pursuing studies to delineate the basis for these chaperone defects in the immune system with age. Employing test agents that increase the activity of chaperones and proteins responsible for removal of aberrant proteins in the aged, we aim to study whether such changes are effective in improving resistance to infectious diseases such as influenza. Results from these studies should provide insight into the role of modulators of these agents in enhancing immune function in the elderly and improving the health-span during senescence. The study section members pointed out that this very innovative application is very significant because understanding aging immunosenescence and establishing new avenues to restore immunologic vigor in the elderly is extremely important.
