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Principal Investigator: STEPHEN C JAMESON
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $2,723,166
Funding agency: National Institute of Allergy and Infectious Diseases
SUMMARY
The association between advanced age and impaired resistance to infections is well known, but poorly
understood. The current COVID-19 pandemic is a clear example of the vulnerability of the elderly to SARS-
CoV-2 infection as well as many other pathogens. Considerable research efforts have shown that components
of both the innate and adaptive immune systems show signs of dysfunction as we age, with signs of both
immunodeficiency, including reduced innate response and poor induction of adaptive immune memory, and
immunopathology including an exaggerated “cytokine storm”. However, while aspects of age-related changes
in immune cells have been explored in depth, the focus has been on defining the nature of dysfunction within
cells of the immune system itself, rather than investigating the potential role of other cell populations in
dominantly compromising immune homeostasis and immunological response to pathogens. Also, although the
increase in immunosenescence with age, defined by cell surface markers for immune cell exhaustion, has
been examined, the extent of cellular senescence in immune cell populations with age and pathogen exposure
remains undefined. Our recent findings indicate that senescent cells (SnCs), including senescent immune
cells, can exert a “bystander” effect on immune cells, provoking immunological dysfunction through secretion of
inflammatory factors, including cytokines and chemokines, termed the “senescence-associated secretory
phenotype” (SASP). We demonstrated that SASP factor production is increased when SnCs or mice containing
SnCs are exposed to pathogens or microbial products that induce innate immune activation. Exposure of old
mice to normal microbial experience (NME) housing resulted in 100% mortality compared to no mortality in
young mice. However, reducing the senescent cell burden in aged mice before or following pathogen exposure
reduced the spread of senescence, the cytokine storm and overall mortality. These results suggests that SnCs,
acting at least in part through SASP factors, can increase peripheral senescence and immune dysfunction
following pathogen exposure. Moreover, viral infection itself drives senescence, termed virus induced
senescence, in mice and humans. Using mouse models in which cellular senescence is induced specifically in
immune cells, we also demonstrated that senescent immune cells drive immunological dysfunction and
secondary senescence and pathology in non-lymphoid tissues. Thus, our overarching hypothesis is that
senescent cells, including senescent immune cell types, dominantly compromise innate and adaptive immune
cell homeostasis in both lymphoid and non-lymphoid organs and reactivity to pathogens. Importantly, we also
hypothesize that these adverse effects can be reversed by SnC elimination with senolytics, providing a new
therapeutic strategy to restoring immune function in the aged. We propose to test these hypotheses in our
PPG application entitled “The role of senescent cells in dysregulating immune responses and pathogen
control”, consisting of three collaborative projects and three integrated cores.
Terms: <AD dementia><Ablation><Adaptive Immune System><Address><Adverse effects><Affect><Age><Age Distribution><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Autoregulation><Bio-Informatics><Bioinformatics><Biology of Aging><Body Tissues><Bystander Effect><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 virus infection><COVID-19 years><COVID19 infection><COVID19 patient><COVID19 positive patient><Cell Aging><Cell Body><Cell Function><Cell Physiology><Cell Process><Cell Senescence><Cell Surface Antigens><Cell surface><Cells><Cellular Aging><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Cellular Senescence><Chemotactic Cytokines><Clinical Trials><Data><Defect><Degenerative Arthritis><Degenerative polyarthritis><Drugs><Dysfunction><Elderly><Exposure to><Functional disorder><GEM model><GEMM model><Generations><Genetic Models><Genetically Engineered Mouse><Homeostasis><Homologous Chemotactic Cytokines><Housing><Human><Immune><Immune Cell Activation><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune memory><Immune response><Immune system><Immunes><Immunodeficiency and Immunosuppression Disorders><Immunologic Diseases><Immunologic Memory><Immunologic Surface Markers><Immunological Diseases><Immunological Dysfunction><Immunological Memory><Immunological Surface Markers><Immunological System Dysfunction><Immunological response><Impairment><Infection><Inflammatory><Innate Immune System><Intercrines><Interruption><Lymphoid><Mediating><Medication><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><NIAID><National Institute of Allergy and Infectious Disease><Nature><Organ><Organism><Osteoarthritis><Osteoarthrosis><Outcome><Pathology><Peripheral><Pharmaceutical Preparations><Physiological Homeostasis><Physiopathology><Population><Primary Senile Degenerative Dementia><Process><Production><Replicative Senescence><Reporting><Research><Resistance><Resistance to infection><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2 infection><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SIS cytokines><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Standardization><Subcellular Process><Surface Antigens><Testing><Tissues><Translating><Viral Diseases><Virus><Virus Diseases><Work><acquired immune system><advanced age><age associated><age associated alterations><age associated changes><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age linked><age related><age related alterations><age related changes><age specific><age specific alterations><age specific changes><aged><aged mice><aged mouse><ages><alterations with age><anamnestic reaction><cell type><changes with age><chemoattractant cytokine><chemokine><clinical applicability><clinical application><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 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus patient><cytokine><cytokine release syndrome><cytokine storm><degenerative joint disease><drug/agent><elderly mice><exhaustion><experience><fighting><frailty><genetically engineered mouse model><genetically engineered murine model><geriatric><host response><hypertrophic arthritis><hypoimmunity><immune activation><immune clearance><immune deficiency><immune elimination><immune function><immune senescence><immune system response><immunodeficiency><immunopathology><immunoresponse><immunosenescence><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><infection resistance><living system><microbial><microbial products><mortality><mouse model><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><old mice><osteoarthritic><pathogen><pathogen exposure><pathophysiology><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><pre-clinical study><preclinical study><primary degenerative dementia><resistant><response><secondary immune response><senescence><senescence associated secretome><senescence associated secretory phenotype><senescent><senescent cell><senile dementia of the Alzheimer type><senior citizen><senolytics><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><single cell analysis><social role><viral infection><virus infection><virus-induced disease>