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：
10617844
负责人：
Jonathan Wanagat
金额：
$ 41.69万
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/10617844
关键词：
Acceleration Affect Age Aging Biological Biological Aging Biological Assay Biopsy Blood Brain Caloric Restriction Cardiovascular Diseases Cause of Death Cell Death Cell Death Induction Cell physiology Cells Cerebrospinal Fluid Cessation of life Chronology Clinical Clinical Trials Clonal Deletion Collaborations DNA 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 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 risk prediction 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Geroscience的进步，必须将衰老视为可修改的风险因素死亡。针对人衰老的干预措施正在进行中，但是缺乏预测性生物标志物衡量这些干预措施的有效性。随着年龄的增长，线粒体DNA（mtDNA）删除在各种组织中的单个细胞内积聚。达到高细胞内丰度，mtDNA缺失破坏氧化磷酸化，细胞功能，并导致细胞死亡。我们假设人mtDNA缺失频率预测了发病率和死亡率的风险，并响应改变HealthSpan的干预措施。我们开发了一种数字PCR分析，该测定法使用总DNA样品量化mtDNA缺失频率来自啮齿动物和人类的任何组织。该测定法提供了绝对定量，可适合96孔格式与随后的细胞表型（包括细胞死亡）密切相关，并具有检测限制至百万份以下一部分。 mtDNA缺失突变频率随着年龄的增长而成倍增加，这增加与年龄诱导的功能失调细胞，组织变性和死亡率的积累相似之处。这项目将进一步发展并验证mtDNA缺失频率，以衡量人类衰老的细胞死亡。我们正在根据FDA的生物分析测定指南验证测试。我们正在测量在人类寿命的许多人体组织和生物流体中的mtDNA缺失频率，将会建立mtDNA缺失频率，年代年龄，临床和生理之间的关系结果和针对人类衰老的干预措施。