Impact of Senolytics on Aged Vaccine Responses

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PROJECT SUMMARY Despite widespread vaccination, influenza (flu) remains a leading cause of death among older adults. Vaccination is the most effective way to prevent infectious disease. However, older adults have dysregulated immune responses that reduce vaccine efficacy and leave them at risk for severe infection and death. Older adults have reduced T cell proliferation, impaired B cell responses, and decreased antibody titers following flu vaccination. Current methods to improve vaccine efficacy in older adults target singular deficits in immune responses and fail to completely rescue responses. Vaccination requires a complex coordination of multiple cell types and tissues; thus an approach that targets the overall biology of aging, in line with the geroscience hypothesis, may be more appropriate for improving vaccine protection and immune responses in older adults. Senescent cell accumulation is a hallmark of aging and evident in various tissues with age. Although these cells are characterized by a mostly irreversible state of cell cycle arrest, they remain metabolically active and importantly, secrete a heterogeneous cocktail of inflammatory cytokines and chemokines that contribute to tissue dysfunction and damage that is coined senescence associate secretory phenotype (SASP). Accumulation of senescent cells and SASP create pro-inflammatory environments and have a causal role in many age-related disorders. CD4 T cells and B cells, the main cells responsible for robust vaccination responses, are extremely sensitive to their microenvironments. Thus, we propose that accumulation of senescent cells and their SASP drive diminished vaccination responses with aging. Importantly, drugs that specifically kill senescent cells, termed senolytics, have been developed and require only intermittent administration to eliminate senescence cells and mitigate the SASP. The safety and efficacy of senolytics have been shown in mouse studies and can alleviate a range of age-related diseases. Human pilot studies have supported their safety and clinical utility in certain pathologies. However, the impact of senolytics on vaccination responses in aged populations has not yet been examined. The overall hypothesis in this proposal is that senescent cells and the SASP play a causal role in impaired flu vaccination responses with aging and that pharmacological clearance of senescent cells will improve vaccination responses. We will test this hypothesis by treating young and aged mice with senolytic drugs prior to vaccination. We will utilize two different vaccination methods, recombinant flu nucleoprotein to induce protective immunity and adjuvanted inactivated flu to induce neutralizing immunity, and then infect mice with flu to interrogate both cell-mediated and humoral vaccination responses. Additionally, we will test our hypothesis in human cells by determining how senescent cell conditioned media impact human T and B cells responses in culture. These approaches will allow us to examine the role of cellular senescence in impaired vaccination responses with aging and investigate the translational utility of senolytic drugs as a pre-vaccination adjuvant.