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Principal Investigator: Andrew R DiNardo
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $614,367
Funding agency: National Institute on Aging
Project Summary:
Last year in the United States, there were 1.3 million cases of pneumonia (excluding
covid19). Worldwide, last year, there were 49 million cases respectively. Even after successful
therapy, pneumonia and other severe infections are associated with >3-fold increased mortality
risk due to increased cardiovascular disease, cancer, and recurrent infections.
Preliminary evidence by our group and others have demonstrated that these severe
infections induce detrimental premature epigenetic scars that accelerate age-associated
epigenetic perturbations and induce pathologic inflammation and decrease immune
responsiveness. While other studies have identified post-infectious premature aging, this study
will be the first to identify which post-infectious premature aging epigenetic scars are associated
with post-infectious mortality, inflammation and decreased immune responsiveness.
We previously identified that post-infectious detrimental epigenetic scars last at least 6
months. Studies with longer-term follow up have confirmed these epigenetic scars are still
present 82 weeks after resolution of the original insult. Therefore, we will follow participants with
severe pneumonia for 24-months after completion of successful therapy and make use of
cutting-edge single cell sequencing to clarify how these detrimental scars are persistently
propagated.
Our preliminary in vitro data demonstrates that infection induced premature epigenetic
aging and immune perturbations can be mitigated by drugs that inhibit the TCA cycle such as
metformin, everolimus, and metformin. This study will implement mechanistic studies to explore
how inhibitors of the TCA can be used to alleviate post-infectious premature epigenetic scars
and restore immune responsiveness.
Terms: <2-ketoglutarate><2-oxoglutarate><Active Follow-up><Aging><Animal Model><Animal Models and Related Studies><Animals><Bacterial Pneumonia><Benchmarking><Best Practice Analysis><Bio-Informatics><Bioinformatics><COVID-19><CV-19><Cancers><Cardiovascular Diseases><Cell Aging><Cell Body><Cell Senescence><Cells><Cellular Aging><Cellular Immune Function><Cellular Senescence><Cessation of life><Cicatrix><Citric Acid Cycle><Clinical><Coronavirus Infectious Disease 2019><DNA><DNA Methylation><Data><Death><Deoxyribonucleic Acid><Dimethylbiguanidine><Dimethylguanylguanidine><Drugs><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Exclusion><Genome><Glean><Human><Hypermethylation><Immune><Immunes><Immunity><In Vitro><Individual><Infection><Inflammation><Krebs Cycle><Malignant Neoplasms><Malignant Tumor><Medication><Metformin><Modeling><Modern Man><N,N-dimethyl-imidodicarbonimidic diamide><Outcome><Participant><Pathologic><Patients><Pharmaceutical Preparations><Pneumonia><Population><Premature Aging><Premature aging syndrome><Progenitor Cells><RNA Seq><RNA sequencing><RNAseq><Recovery><Replicative Senescence><Resolution><Risk><SDZ RAD><Scars><Sepsis><Severity of illness><Single cell seq><Succinates><Survivors><T-Cells><T-Lymphocyte><TCA cycle><Testing><Tricarboxylic Acid Cycle><Tricarboxylic Acids><United States><Viral Pneumonia><Work><accelerated aging><accelerated biological age><accelerated biological aging><active followup><age acceleration><age associated><age correlated><age dependent><age linked><age related><age specific><aging induced epigenetic change><aging-associated epigenetic change><aging-related epigenetic change><alpha ketoglutarate><alpha-oxoglutarate><application in practice><bacteria pneumonia><benchmark><blood infection><bloodstream infection><cardiovascular disorder><clinical relevance><clinically relevant><cofactor><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><death risk><disease severity><drug/agent><epigenetic aging><epigenetic mechanisms in aging><epigenetic modifications in aging><epigenetic regulation of aging><epigenetically><epigenome><epigenomics><everolimus><exhaust><experiment><experimental research><experimental study><experiments><follow up><follow-up><followed up><followup><immune function><improved><in vivo><infection recurrence><inhibitor><malignancy><model of animal><mortality><mortality risk><mouse model><murine model><mycobacterial><neoplasm/cancer><patient retention><practical application><premature><prematurity><preservation><prevent><preventing><progenitor><recurrent infection><recurring infection><resolutions><single cell next generation sequencing><single cell sequencing><stem cells><thymus derived lymphocyte><transcriptome sequencing><transcriptomic sequencing><α-ketoglutarate><α-oxoglutarate><αKG>