Abstract: Aging represents a prominent risk factor for infection-related mortality. This heightened susceptibility to infection is closely associated to the attenuation of both strength and durability of humoral responses in elderly humans and mice following vaccination. Extensive clinical and fundamental aging research point to a few mechanisms attributing to immune dysfunction, yet antibody titers are reduced and tend to decay faster. Plasma cells (PCs) are rare, radiation resistant, terminally differentiated B cells responsible for maintaining long lasting serological memory. With aging, PCs accumulate, however it does not correlate to enhanced protection. Thus, PCs may play a detrimental role during vaccine responses in the elderly. Within the bone marrow (BM) niche, PCs demonstrate a ‘stop and go’ motility pattern, allowing them to freely navigate in the BM and assemble into or disassemble from clusters. A subset of PCs known for their ability to survive for years in humans and mice are recognized as long-lived PCs (LLPCs). Intravital imaging of mouse BM LLPCs reveals that they are arrested in survival clusters, which we have found are not formed in APRIL-deficient mice, a critical cytokine involved in PC longevity. With aging, human-derived BM morphonuclear cells express, produce, and secrete reduced levels of APRIL. Moreover, the increase in TNFα and other pro-inflammatory cytokines with aging, or inflamm-aging, may contribute to increased pressure for survival of newly generated PCs but not LLPCs after vaccination. While PCs accumulate with age, preliminary data from our lab indicates that LLPCs are enriched in the PC pool of elderly mice. Thus, my overall hypothesis is that, with aging, the accumulation of LLPCs dysregulates humoral immunity through competition against nascent PCs. I aim to test this hypothesis in numerous and robust ways. By using adult (3–5 month old) and elderly (20-24 month old) C57B6/J mice, unique genetic tools targeting PCs, 2-photon intravital imaging, spectral flow cytometry, and high through-put sequencing, I will be able to enumerate the accumulation of BM LLPCs and comprehensively demonstrate competition between pre-existing PCs and nascent PCs. Ultimately, this study proposes a novel competition model and the first ever single cell-RNA sequencing library on aging PCs. The outcomes of this study can lead to an improvement in current vaccinations for elderly individuals or tailored vaccines for this demographic.