Mitochondrial genetics of exceptional longevity in multigeneration matrilineages

多代母系中超长寿命的线粒体遗传学

基本信息

批准号：
8865513
负责人：
RICHARD Moore CAWTHON
金额：
$ 29.6万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8865513
关键词：
Adult Affect Age Aging Amino Acid Sequence Amino Acid Substitution Amino Acids Balaena Basal metabolic rate Biochemical Pathway Biochemistry Bioinformatics Biological Biological Markers Blood Categories Caucasians Cell Line Cells Cessation of life Code Codon Nucleotides Consensus Sequence Cultured Cells Cysteine DNA DNA Sequence Analysis DNA copy number Data Databases Development Diet Direct Repeats Disease Elderly European Evolution Exhibits Functional disorder Funding Future Gene Expression Genealogy Genes Genetic Genome Stability Genomics Germ-Line Mutation Guanine + Cytosine Composition Health Heat Stress Disorders Human Individual Inherited Intervention Investigation Length Life Life Style Longevity Mammals Measures Medical Mentored Research Scientist Development Award Mitochondria Mitochondrial DNA Molecular Molecular Profiling Mutation Nuclear Oxygen Pattern Peptide Sequence Determination Pharmacologic Substance Polymerase Chain Reaction Population Population Database Production Proteins Publishing Reactive Oxygen Species Recombinant DNA Research Resistance Ribosomal DNA Ribosomal RNA Risk Role Sampling Shrews Somatic Mutation Structure Testing Threonine Time Tissues Transfer RNA Utah Variant Whole Blood Yeasts age related aging population design effective intervention gene therapy genetic pedigree genome integrity improved lymphoblastoid cell line middle age mitochondrial DNA mutation mitochondrial genome mortality population based protein structure senescence stoichiometry telomere theories tool

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop medical interventions to delay and/or slow aging, and thereby increase the number of years of healthy adult life (YHL). The interventions that have been validated in extending the adult healthspan of mammals to date (dietary, life style, pharmacologic, or genetic) have provided approximately a two-fold increase in YHL at best. Yet evolution, via unidentified genetic changes, has produced a 200-fold range of Maximum Lifespan (MLS) across mammalian species: from about one year for the shrew to over 200 years for the bowhead whale. Once we discover the genetic and biochemical pathways by which evolution has achieved such huge differences in YHL across species, then we may be able to design effective interventions to dramatically boost the human healthspan. Recently published studies suggest that mitochondrial sequence features (only some of which change protein structure) may be responsible for up to half of the variation in MLS across species, with remaining variation statistically attributable to differences in Resting Metabolic Rate (RMR) and/or body mass (which is highly correlated with RMR). No published studies have investigated whether mtDNA sequence features associated with MLS of species are also associated with variation in lifespan in normal human populations. Furthermore, the few mitochondrial sequence variants known to be associated with human longevity have not yet been tested for association with other biomarkers that vary with MLS of species (e.g. reactive oxygen species (ROS) production rates, cellular resistance to heat stress, and mtDNA mutation rates). With previous NIA funding under the P.I.'s K01 award (1997-2002), we screened a large genealogical database (the Utah Population Database) for mitochondrial lineages (matrilineages) in which exceptional human longevity was clustering, and collected whole blood DNA samples and lymphoblastoid cell lines from 55 such matrilineages. Analyses of the DNA sequences of all protein-coding genes from the mitochondrial genomes of 20 of these matrilineages, and from control mitochondrial genomes, revealed several amino acid changes significantly associated with longevity. We now propose to obtain the complete sequences of the mitochondrial genomes in these 55 longevity-selected matrilineages, and in 141 control matrilineages, and identify all sequence features associated with exceptional longevity. We will also test whether the longevity- selected matrilineages show favorable shifts in three biomarkers of MLS of species: towards lower ROS production rates, higher cellular resistance to heat stress, and lower mtDNA mutation rates. We will also collect comprehensive gene expression profiles, and additional measures of nuclear and mitochondrial genomic integrity, from the longevity-selected and control matrilineages. Bioinformatics tools applied to all available data may identify genetic and biochemical pathways regulating longevity across and within species, and identify possible targets for pharmaceutical and/or gene therapies aimed at delaying and/or slowing aging.

描述（由申请人提供）：这项研究的长期目标是制定医疗干预措施以延迟和/或缓慢的衰老，从而增加健康成人生活的年限（YHL）。在扩展迄今为止哺乳动物的成人健康状态（饮食，生活方式，药理学或遗传学）方面已得到验证的干预措施，最多可以增加YHL两倍。然而，通过未识别的遗传变化进化，跨哺乳动物物种产生了200倍的最大寿命（MLS）：从sh的大约一年到弓头鲸鱼的200多年。一旦我们发现了进化在整个物种中的YHL巨大差异的遗传和生化途径，那么我们也许能够设计有效的干预措施以极大地增强人类HealthSpan。最近发表的研究表明，线粒体序列特征（只有一些变化蛋白结构）可能导致多达一半的物种MLS变化的一半变化，并且在统计学上保持差异归因于静息代谢率（RMR）（RMR）和/或体重的差异（与RMR高度相关）。没有发表的研究研究了与物种ML相关的mtDNA序列特征是否也与正常人种群的寿命变化有关。此外，尚未对与其他生物标志物（例如，反应性氧（ROS）产生速率，对热应激的细胞抵抗力和MTDNA突变率不同的其他生物标志物的相关性，尚未对已知与人寿命相关的线粒体序列变体进行测试。在P.I. K01奖（1997-2002）下的NIA资金之前，我们筛选了一个大型的族谱数据库（犹他州人口数据库），以介绍线粒体谱系（矩阵），其中特殊的人类寿命是人类的寿命是聚集的，并收集了整个血液DNA样品和lymphophoblebblasofiod cill in 55 cellirine 55555555555555。对这些基因组的线粒体基因组的所有蛋白质编码基因的DNA序列的分析，以及来自对照线粒体基因组的DNA序列，揭示了几种与寿命显着相关的氨基酸变化。现在，我们建议在这55个寿命选择的基质中获得线粒体基因组的完整序列，并在141个对照矩阵中，并识别与特殊寿命相关的所有序列特征。我们还将测试在三种MLS物种的生物标志物中，寿命 - 选择的基质中是否表现出有利的变化：朝着较低的ROS产生速率，较高的细胞抗热应力和较低的mtDNA突变率。我们还将从长寿选择和控制基因组的基因组基因组完整性以及控制寿命的基因组完整性和控制基因组完整性的其他措施中收集全面的基因表达谱。应用于所有可用数据的生物信息学工具可以识别调节物种内和内部寿命的遗传和生化途径，并确定旨在延迟衰老和/或减缓衰老的药物和/或基因疗法的可能靶标。