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Metabolome-Genome Associations for Determining Mechanisms of Aging in Drosophila

确定果蝇衰老机制的代谢组-基因组关联

基本信息

批准号：
9268534
负责人：
Daniel Edward Promislow
金额：
$ 36.22万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9268534
关键词：
Affect Age Aging Animal Model Animals Biological Biological Process Data Diet Dietary Factors Disease Dissection Drosophila genome Drosophila genus Drosophila melanogaster Environment Environmental Risk Factor Foundations Gene Expression Genes Genetic Genetic Variation Genetic study Genome Genotype Goals Gold Human Individual Laboratories Lead Life Extension Link Longevity Mammals Maps Measures Mediating Metabolic Metabolic Pathway Methods Molecular Molecular Genetics Organism Other Genetics Pathologic Pathway interactions Phenotype Physiological Polyamines Population Proteome Quantitative Genetics Reagent Role Series Shapes Structure Systems Biology Testing Tissues Transgenic Organisms Tryptophan Metabolism Pathway Variant Work age effect age related base dietary restriction epigenome experimental study fatty acid metabolism feeding fitness fly genotypic sex glucose metabolism glycogen metabolism human disease innovation insight metabolic profile metabolome metabolomics microbiome monoamine novel public health relevance reference genome response senescence sex small molecule therapeutic target tool trait transcriptome

项目摘要

DESCRIPTION (provided by applicant): Why do we age, and why do some individuals age faster than others? Genetic studies have found many genes that can extend lifespan in laboratory populations. However, these genes explain little of the substantial genetic variation in lifespan that we observe in natural populations, including humans. Environmental studies have found that diet restriction (DR) can extend lifespan, and that this effect is highly conserved across taxa. However, within populations, the DR response shows considerable genetic variation. As with lifespan, the pathways that account for this genetic variation in the DR response are also unknown. Our overarching goal is to understand the genetic pathways, functional mechanisms and selective forces that shape this natural variation in aging. Towards this end, we have gathered three important sets of preliminary data. First, we have found that sex, diet, tissue type, genotype, and age all have substantial effects on the fruit fly metabolome. Second, diet restriction, which can extend mean lifespan, leads to a dramatic reversal of the effect of age on the metabolome, and this reversal appears to be associated with glycogen, glucose, and tryptophan metabolism. Third, diet restriction extends lifespan in some genotypes, while in others there is no response at all. Based on these data, we hypothesize that genetic and environmental factors that extend lifespan do so predominantly by slowing age-related changes in metabolic pathways, and that variation in these pathways will allow us to a) predict the longevity of a genotype; b) predict whether lifespan in a given genotype will respond to DR; and c) discover the mechanisms through which DR extends lifespan. Specifically, we hypothesize that DR will extend lifespan by slowing age-related changes in the same molecular pathways that account for natural variation in longevity. We will test our hypotheses by genetically mapping the metabolome in a population that shows significant variation in rates of aging, and by identifying the causal metabolic pathways that determine how individual genotypes respond to DR. Finally, we will take advantage of the power of fly genetics to manipulate metabolite levels and gene expression in flies. These manipulations will allow us to test specific mechanistic hypotheses that arise from our preliminary studies and from results generated by the work proposed here. This innovative approach combines highly sensitive metabolomic profiling with both quantitative and molecular genetics in an easily manipulated model organism, allowing us to understand the molecular mechanisms that underlie natural variation for aging and aging-related perturbations at an unprecedented scale and level of detail. This work is expected to provide critical insights into the functional mechanisms by which well-studied factors increase lifespan, and to lead to a clearer understanding of how variation in fitness traits is generated and maintained in natural populations. The metabolomic profiling proposed here can also be carried out easily in human populations, and as such, our approach has the long- term potential to reveal the molecular pathways associated with aging and age-related disease in humans.