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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.

项目摘要/摘要由于老年科学的进步，老龄化必须被认为是导致以下疾病的主要原因的一个可改变的风险因素死亡。针对人类衰老的干预正在进行中，但缺乏预测生物标记物来衡量这些干预措施的有效性。随着年龄的增长，体细胞衍生的线粒体DNA(MtDNA) 缺失基因在不同组织的单个细胞内以克隆性方式积累。达到高细胞内线粒体DNA的大量缺失会破坏氧化磷酸化，破坏细胞功能，导致细胞死亡。我们假设人类线粒体DNA缺失频率预测发病和死亡的风险，并对改变健康寿命的干预措施。我们已经开发出一种数字聚合酶链式反应方法，可以用总的dna样本来量化mtdna的缺失频率。从啮齿动物和人类的任何组织中提取。这项化验提供了绝对定量，适用于96井格式，与随后的细胞表型(包括细胞死亡)密切相关，并具有检测到限制在百万分之一以下。线粒体DNA缺失突变频率随着年龄的增长呈指数增加，这增加与年龄导致的功能障碍细胞堆积、组织退化和死亡率平行。这该项目将进一步开发和验证线粒体DNA缺失频率，以此作为衡量人类衰老过程中细胞死亡的指标。我们正在根据FDA的生物分析测试指南对该测试进行验证。我们正在测量线粒体DNA在人体组织和体液中的缺失频率在人的一生中和将建立线粒体DNA缺失频率与实际年龄、临床和生理的关系结果，以及针对人类老龄化的干预措施。