Immunosenescence of primary lymphatic organs is characterized by a decrease in the self-renewing potential of precursor cells as well as generation of lineage-committed cells affected by age-related changes. The consequences of this immune decline are increased susceptibility to infections and cancer, and reduced responses to vaccinations. Thus far a successful therapeutic intervention for immunosenescence remains elusive, despite the vast potential benefit of such therapy. To address this issue, we initiated a study mapping age-related changes in hematopoietic cells in an effort to determine which changes might be amenable to therapeutic intervention. We found that a hallmark of bone marrow cell precursors (CD34+), as well as lineage committed antigen presenting cells (B cells and conventional dendritic cells (cDC)) from aged populations, is the presence of an extensively glycated, carbonylated and lipoxidated proteome. We hypothesize that the modified proteome contributes to immunosenescence by compromising the overall cellular functionality and intracellular pathways required to mount effective immune responses. To test this hypothesis we will focus on cDC functionality in aging mice. In particular we propose to use a series of biochemical and biophysical approaches to determine in a quantitative manner how the increasingly carbonylated proteome and endosomal accumulation of aggregates of glycated, lipoxidated and carbonylated proteins interfere with MHC class II restricted immune functions. In vivo and in vitro experiments will be performed on cDC from mice of three different age groups as well as human donors with an age spanning from 18 to 80 years old, to validate our results in human subjects. Differently from other age-related modifications (e.g., telomere shortening), which cannot be manipulated, we previously demonstrated that the oxidatively damaged proteome was responsive to therapeutic interventions aimed at decreasing its cellular prototoxicity. Thus, MHC II-restricted immune responses will be probed in control conditions as well as following an in vitro and in vivo therapeutic regimen aimed at decreasing the carbonylated proteome We predict that since myeloid cell precursors and cDC have a very short half-life, this makes them a particularly suitable target for decreasing the harmful effect of an extensively carbonylated proteome. The overall fundamental goal is to improve the age-related changes in cellular proteo- toxicity and ultimately improve cDC-mediated adaptive immune responses.
The major long term goal of our study is to fully assess age-related changes in dendritic cells (cDC) immune function which could be harnessed towards the improvement of the immune response in the elderly. A combinatory approach using cDC from mice and humans will indeed evaluate the most effective strategy to increase MHC II-related immune responses. The benefit would be an improvement in the overall efficiency of the immune response towards invading pathogens as well as the poor vaccine response normally associated with aging.
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