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Mitochondrial DNA Deletion Mutation Frequency as a Metric of Biologic Age

线粒体 DNA 缺失突变频率作为生物年龄的指标

基本信息

批准号：
10444851
负责人：
Jonathan Wanagat
金额：
$ 44.49万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444851
关键词：
Affect Age Aging Biological Biological Aging Biological Assay Biopsy Blood Brain Caloric Restriction Cardiovascular Diseases Cause of Death Cell Death Cell physiology Cells Cerebrospinal Fluid Cessation of life Chronology Clinical Clinical Trials Clonal Deletion DNA DNA copy number Deletion Mutation Development Disease Effectiveness of Interventions Electron Transport Equation Evaluation Exercise Fiber Frequencies Funding Genome Geroscience Goals Growth Guidelines Health Heart Human Individual Intervention Intervention Trial Kidney Kidney Diseases Longevity Measures Metabolic Diseases Metformin Methods Mitochondrial DNA Molecular Morbidity - disease rate Muscle Muscle Fibers Neurocognitive Outcome Oxidative Phosphorylation Patients Phenotype Physical Performance Physiological Prediction of Response to Therapy Process Public Health Replication Error Resources Risk Risk Factors Rodent Sampling Skeletal Muscle Skin Solid Spinal Cord Testing Tissue Banks Tissue Sample Tissues Urine Validation Woman anti aging clinical translation clinically relevant detection limit digital disability effectiveness measure experimental study healthspan healthy aging human tissue improved indexing longitudinal human study modifiable risk mortality muscle aging novel predictive marker response sex tissue degeneration treatment trial vastus lateralis

项目摘要

PROJECT SUMMARY/ABSTRACT Due to advances in geroscience, aging must be considered a modifiable risk factor for the major causes of death. Interventions targeting human aging are ongoing, but there is a lack of predictive biomarkers to measure the effectiveness of these interventions. With age, somatically-derived mitochondrial DNA (mtDNA) deletions clonally accumulate within individual cells across a variety of tissues. Attaining high intracellular abundance, mtDNA deletions disrupt oxidative phosphorylation, cellular function, and result in cell death. We hypothesize that human mtDNA deletion frequency predicts the risk of morbidity and mortality and responds to interventions that alter healthspan. We have developed a digital PCR assay that quantifies mtDNA deletion frequency using total DNA samples from any tissue in rodents and humans. This assay provides absolute quantitation, is amenable to a 96-well format, correlates strongly with the subsequent cellular phenotypes including cell death, and has a detection limit below one part per million. MtDNA deletion mutation frequency increases exponentially with age and this increase parallels the age-induced accumulation of dysfunctional cells, tissue degeneration, and mortality. This project will further develop and validate mtDNA deletion frequency as a measure of cell death in human aging. We are validating the test in accordance with FDA guidelines for bioanalytical assays. We are measuring mtDNA deletion frequency in a number of human tissues and biofluids across the human lifespan and will establish the relationship between mtDNA deletion frequency, chronological age, clinical and physiological outcomes, and interventions targeting human aging.

项目总结/文摘