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Principal Investigator: Jenna Bartley
Organization: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
Fiscal Year: 2024
Award: $415,416
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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disease rate><Murine><Mus><Nucleoproteins><Older Population><Pathology><Pathway interactions><Pharmaceutical Preparations><Phenotype><Physiopathology><Pilot Projects><Play><Pneumonitis><Predisposition><Prophylactic vaccination against influenza><Pulmonary Inflammation><Quercetin><Recombinants><Replicative Senescence><Risk><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 vaccine><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><SIS cytokines><Safety><Seahorse><Serum><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 vaccine><Severities><Severity of illness><Spleen><Spleen Reticuloendothelial System><Structure of germinal center of lymph node><Susceptibility><T cell response><T-Cell Proliferation><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Tissues><Vaccinated><Vaccination><Vaccines><Viral><Viral Burden><Viral Load><Viral Load result><access to vaccination><access to vaccines><adult youth><age associated><age associated disease><age associated disorder><age associated impairment><age correlated><age dependent><age dependent disease><age dependent disorder><age dependent impairment><age linked><age related><age related human disease><age specific><age-related disease><age-related disorder><age-related impairment><aged><aged group><aged groups><aged individual><aged individuals><aged mice><aged mouse><aged people><aged person><aged persons><aged population><aged populations><ages><aging population><antibody titering><cell type><chemoattractant cytokine><chemokine><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 vaccine><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 vaccine><cytokine><disease severity><draining lymph node><drug/agent><elderly mice><elongating the lifespan><extend life span><extend lifespan><flow cytophotometry><flu><flu immunisation><flu infection><flu vaccine><flu virus infection><flu virus vaccine><geroscientific><hallmarks of aging><health-span><healthspan><healthy life span><host response><immune modulation><immune regulation><immune response to vaccination><immune response to vaccines><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><inflammatory environment><inflammatory milieu><influenza infection><influenza virus infection><influenza virus vaccination><influenza virus vaccine><lifespan extension><mortality><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><neutralizing antibody><old mice><older adult><older adulthood><older groups><older individuals><older person><pathophysiology><pathway><pharmacologic><pillars of aging><pilot study><population aging><prevent><preventing><programs><pulmonary><regional lymph node><response><senescence><senescence associated secretome><senescence associated secretory phenotype><senescent><senescent cell><senolytics><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><systemic inflammation><systemic inflammatory response><thymus derived lymphocyte><tool><translational impact><vaccination access><vaccination against influenza><vaccination availability><vaccine access><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine against flu><vaccine against influenza><vaccine associated immune response><vaccine availability><vaccine candidates against SARS-CoV-2><vaccine efficacy><vaccine for novel coronavirus><vaccine immune response><vaccine immunogenicity><vaccine induced immune response><vaccine response><vaccine responsiveness><vaccine-induced response><vaccines preventing COVID><vaccines to prevent COVID><young adult><young adulthood>