Aging is the leading risk factor for Alzheimer's Disease (AD) and many other chronic diseases, with more than 6.5 million cases of AD in the US. Regulating or slowing cellular aging, particularly in microglia and astrocytes that regulate neuroimmunity, would have a major impact on the treatment of AD, but the proteins that control cellular aging processes are poorly understood. Cellular aging has been characterized into 9 "hallmarks" or phenotypes that define aged cells. Most hallmarks are a result of cellular stress, such as DNA damage and oxidation, and are inter-related in both their causes and outcomes. The cellular aging process is linked to dramatically altered gene expression, which is largely controlled by transcription factors (TFs). Longevity studies between species also suggest that TF activity can define the rate of aging. We hypothesize that TFs can modulate cellular aging and that identifying the TFs that play a role in aging processes will enable an entirely new generation of therapeutic targets with the potential to treat, delay, and possibly even prevent AD. The discovery of TFs that can improve the lifespan of patients would have a profound impact on the prevention and treatment of AD and many other diseases.
Public Health Relevance Statement: PROJECT NARRATIVE The human health significance of the proposed work is the identification of new targets for Alzheimer's Disease (AD) and other diseases by identifying transcription factors (TFs) that can slow cellular aging. Currently, no drug on the market targets the underlying disease process of AD, and therapeutics against traditional targets in AD have repeatedly failed in late-stage clinical trials. The lack of AD treatments and the high co-morbidity of aging and chronic disease highlight an urgent need to identify new therapeutic targets. The mechanisms of aging uncovered in our studies ultimately will be translated into therapeutics as nutritional, pharmacological, or gene therapy interventions targeting either the TFs themselves or the gene products and pathways controlled by the TFs. The ability to rapidly reprogram and create engineered cells also has a large platform potential for identifying other drug targets, creating engineered cell therapeutics, and improving biologics manufacturing.
Project Terms: Abbreviations; Aging; Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Antibodies; Astrocytes; Astrocytus; Astroglia; astrocytic glia; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Products; Biologic Products; Biological Agent; biologics; biopharmaceutical; biotherapeutic agent; Cell Aging; Cell Senescence; Cellular Aging; Cellular Senescence; Replicative Senescence; Cells; Cell Body; Chronic Disease; Chronic Illness; chronic disorder; Clinical Trials; comorbidity; co-morbid; co-morbidity; Disease; Disorder; DNA Damage; DNA Injury; DNA Repair; DNA Damage Repair; Unscheduled DNA Synthesis; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Engineering; Future; Gene Expression; gene therapy; DNA Therapy; Gene Transfer Clinical; Genetic Intervention; gene repair therapy; gene-based therapy; genetic therapy; genomic therapy; Genes; Health; Human; Modern Man; Libraries; Longevity; Length of Life; life span; lifespan; Methods; Mitochondria; mitochondrial; Biological Models; Biologic Models; Model System; Molecular Conformation; Molecular Configuration; Molecular Stereochemistry; conformation; conformational state; oxidation; Patients; Pharmacology; Phenotype; Plasmids; Play; Proteins; Viral Receptor; Virus Receptors; social role; Role; Progenitor Cells; stem cells; T-Cells; thymus derived lymphocyte; T-Lymphocyte; Technology; Testing; transcription factor; Basal Transcription Factor; Basal transcription factor genes; General Transcription Factor Gene; General Transcription Factors; Transcription Factor Proto-Oncogene; Transcription factor genes; Transfection; Translating; Work; Generations; telomere; TimeLine; Reactive Oxygen Species; Active Oxygen; Oxygen Radicals; Pro-Oxidants; base; cell age; improved; Microglia; Hortega cell; gitter cell; mesoglia; microglial cell; microgliocyte; perivascular glial cell; Link; Oxidative Stress; Therapeutic; Reporter; DNA Methylation; programs; Source; Cellular Regulation; cell growth regulation; membrane structure; Membrane; expression vector; Prevention; Proteome; intervention therapy; Therapeutic Intervention; Modeling; Genomic Instability; Genome Instability; preventing; prevent; Cellular Transformation; metaplastic cell transformation; IRES; Internal Ribosome Entry Segment; Ribosome Entry Site; Internal Ribosome Entry Site; Receptor Cell; Cellular Stress; cell stress; Epigenetic Process; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Nutritional; nutritious; Monitor; Process; Pathway interactions; pathway; Outcome; Stress Tests; mitochondrial dysfunction; Alzheimer's disease risk; Alzheimer risk factor; alzheimer risk; mouse model; murine model; therapeutic target; new therapeutic target; new drug target; new druggable target; new pharmacotherapy target; new therapy target; novel drug target; novel druggable target; novel pharmacotherapy target; novel therapeutic target; novel therapy target; Biological Markers; bio-markers; biologic marker; biomarker; stem cell biology; phase 2 study; phase II study; Drug Targeting; targeted treatment; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; methylation biomarker; methylation marker; gene product; proteostasis; protein homeostasis; immune checkpoint; immune check point; immunecheckpoint; healthspan; health-span; Alzheimer's disease therapeutic; Alzheimer's therapeutic
