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Principal Investigator: LAURA Jane NIEDERNHOFER
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $541,140
Funding agency: National Institute of Allergy and Infectious Diseases
Senescent cells (SnCs) increase in tissues with age and are established to play a causal role in aging and age-
related conditions/syndromes. SnCs confer their adverse effects, at least in part, through their senescence-
associated secretory phenotype (SASP), which is pro-inflammatory. A particularly debilitating, deadly, and costly
condition that plagues the elderly is susceptibility to severe morbidity and mortality upon infection. The recent
SARS-CoV-2 pandemic illuminated this problem dramatically. Why are older COVID-19 patients at higher risk
(>350X) of cytokine storm, multi-organ failure and death upon infection with SARS-CoV-2 compared to younger
individuals? Similarly, why are the elderly more susceptible to progression to sepsis and acute respiratory
distress syndrome upon infection? We hypothesize it is because of the increased SnC burden in the elderly with
their inflammatory SASP that drives chronic sterile inflammation and dysregulates the innate and adaptive
immune responses of older individuals with infection. We developed a novel experimental paradigm in which to
test this hypothesis called normal microbial experience (NME). Specified pathogen-free (SPF) mice are exposed
to pet store as a model of “community acquired infections.” The pet store mice carry mouse hepatitis virus (MHV),
a ß-coronavirus closely related to SARS-CoV-2. Young SPF survive NME, but old mice experience 100%
mortality within two weeks. This is due to an increased inflammatory response in old mice compared to young
upon NME exposure. Pharmacologic or genetic approaches to clear SnCs after NME reduced mortality of old
mice by 50% and improved adaptive immunity against MHV. We found that in vitro and in vivo, SnCs hyper-
respond to challenge with pathogen-associated molecular patterns compared to healthy cells, leading to
increased expression of inflammatory cytokines/chemokines. Additionally, we found that senescent immune cells
are particularly deleterious and able to drive secondary senescence and tissue damage through both gain-of
function and loss-of function mechanisms. While provocative, there remains large gaps in knowledge, which if
addressed offer completely novel approaches to improving immune function and preventing severe infections
in the elderly. Here, we propose to identify the senescent immune and other SnC type(s) that impede resilience
to pathogens in old mice and the mechanism(s) involved. To prove cause and effect and move towards
translation, we propose in this Project to identify the key SnCs as possible therapeutic targets and optimize
senotherapeutic drugs to improve the immune response in aged mice. To address the role of SnCs in driving
immune dysfunction, the Specific Aims of Project 1 are: 1) To identify the SnCs that drive adverse outcomes and
immune dysfunction upon exposure of aged mice to environmental microbes, viral infection, or LPS; 2) To
determine if removal of SnCs is sufficient to prevent mortality and improve immune function upon exposure of
mice to environmental pathogens, viral infection, or LPS; and 3) To optimize senotherapeutic strategies to
improve the immune response of aged mice.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><AP20187><Abscission><Address><Adipocytes><Adipose Cell><Adoptive Transfer><Adverse effects><Age><Aging><Animals><Astrocytes><Astrocytus><Astroglia><Automobile Driving><Blood Serum><Body Tissues><Brain><Brain Nervous System><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CDK4I><CDKN2><CDKN2 Genes><CDKN2A><CDKN2A gene><CMM2><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 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 virus><COVID-19 years><COVID19 patient><COVID19 positive patient><COVID19 virus><CRE Recombinase><Cell Body><Cell Function><Cell Isolation><Cell Physiology><Cell Process><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Cessation of life><Chemotactic Cytokines><Chronic><CoV-2><CoV2><Community-Acquired Infections><Cyclin-Dependent Kinase Inhibitor 2A Gene><Cytotoxic cell><DNA Repair Gene><DNA repair protein><Data><Death><Dose><Drugs><Dysfunction><Elderly><Encephalon><Enterobacteria phage P1 Cre recombinase><Equation><Excision><Exposure to><Extirpation><Fat Cells><Fats><Fatty acid glycerol esters><Foundations><Functional disorder><Genotoxic Stress><Heart><Hematologic Body System><Hematologic Organ System><Hematopoietic Body System><Hematopoietic System><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Homologous Chemotactic Cytokines><Human><INK4><INK4A><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immune system><Immunes><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunologically><Immunologics><In Vitro><Individual><Infection><Inflammation><Inflammatory><Inflammatory Response><Innate Immune Response><Intercrines><K lymphocyte><Kidney><Kidney Urinary System><Knowledge><Laboratory mice><Life><Lipocytes><Liver><Liver Cells><MOF syndrome><MTS1><MTS1 Genes><Macrophage><Mature Lipocyte><Mature fat cell><Measures><Medication><Mice><Mice Mammals><Microbe><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Mouse Hepatitis Coronavirus><Mouse Hepatitis Virus><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Murine Gastroenteritis Virus><Murine hepatitis virus><Mus><Mφ><NK Cells><Natural Killer Cells><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Older Population><Organ><Organism><Organism-Level Process><Organismal Process><Pattern><Pharmaceutical Preparations><Physiologic Processes><Physiological Processes><Physiopathology><Play><Predisposition><Removal><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Senotherapeutic><Sepsis and ARDS><Serology><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Specific qualifier value><Specified><Splenocyte><Sterility><Subcellular Process><Surgical Removal><Susceptibility><Syndrome><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TP16><TSG9A><Testing><Therapeutic><Tissues><Transgenic Organisms><Translations><Viral Diseases><Virus><Virus Diseases><Wild Type Mouse><Work><Wound Repair><Wuhan coronavirus><acute respiratory distress syndrome caused by sepsis><adaptive immune response><adaptive immunity><advanced age><adverse consequence><adverse outcome><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 associated><aging population><aging related><astrocytic glia><bacteriophage P1 recombinase Cre><beta CoV><beta coronavirus><betaCoV><betacoronavirus><cell sorting><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 infected patient><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><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 disease-19 virus><coronavirus patient><cost><cytokine><cytokine release syndrome><cytokine storm><driving><drug/agent><elderly mice><experience><gain of function><genetic approach><genetic strategy><geriatric><hCoV19><hepatic body system><hepatic organ system><high risk><host response><immune function><immune system response><immunoresponse><improved><in vivo><innovate><innovation><innovative><life span><lifespan><living system><logarithm><logarithmic><loss of function><microbial><mortality><multiorgan failure><multiple organ system failure><murine hepatitis coronavirus><nCoV2><natural aging><neuronal><new approaches><normal aging><normative aging><novel><novel approaches><novel strategies><novel strategy><old mice><older groups><older individuals><older person><p14ARF><p16 Genes><p16INK4 Genes><p16INK4A Genes><p16INK4a><pathogen><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><pharmacologic><population aging><prevent><preventing><renal><resection><resilience><resilient><senescence><senescence associated secretome><senescence associated secretory phenotype><senescent><senescent cell><senior citizen><sepsis ARDS><sepsis acute respiratory distress syndrome><sepsis and acute respiratory distress syndrome><sepsis associated acute respiratory distress syndrome><sepsis induced ARDS><sepsis induced acute respiratory distress syndrome><sepsis related acute respiratory distress syndrome><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><social role><sterile><therapeutic target><thymus derived lymphocyte><transgenic><translation><viral infection><virus infection><virus-induced disease><wildtype mouse><wound healing><wound recovery><wound resolution><β CoV><β coronavirus><βCoV>