Sex-Specific Aging Mechanisms

性别特异性衰老机制

基本信息

批准号：
10171744
负责人：
JOHN Gerard TOWER
金额：
$ 37.13万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171744
关键词：
3-Dimensional Aging Alzheimer&apos s Disease Amino Acids Autoimmune Diseases Bacteria Bacterial Toxins Caenorhabditis elegans Cardiovascular Diseases Catecholamines Cells Cholesterol Homeostasis Collaborations Core Facility Data Diabetes Mellitus Disease Dopamine Drosophila genus Drug Antagonism Enzymes Estrogens Female Future Gene Expression Genes Genetic High-Throughput Nucleotide Sequencing Hormones Human Immune Inflammation Intervention Laboratories Link Longevity Maintenance Malignant Neoplasms Malondialdehyde Metabolic Metabolic Pathway Metabolism Methods Microbe Microbial Genome Sequencing Mifepristone Mitochondria Octopamine Osteoporosis Oxidative Stress Parkinson Disease Partner in relationship Pathway interactions Peptides Pharmaceutical Preparations Pregnancy Production Publishing Quick Test for Liver Function Reagent Regulation Regulator Genes Reporter Reproduction Research Role Seminal Sex Bias Sex Differentiation Shock Signal Transduction Signaling Protein Steroids Stroke Testing Tissues Transgenic Organisms Universities Washington Woman X Inactivation behavior test chemical genetics commensal bacteria experimental study feeding fly genetic analysis genetic manipulation healthspan hormonal signals human disease human female immune function lipid metabolism male men metabolome metabolomics microbial microbiome microbiome alteration microbiome analysis mitochondrial metabolism purine metabolism reconstitution reproductive sex sexual dimorphism small molecule steroid hormone transcriptome

项目摘要

Summary Sex bias in human disease is common, however underlying mechanisms remain unclear. Women have immune advantage relative to men, but also greater auto-immune disease and Alzheimer's Disease. Women's immune advantage is modulated by pregnancy and correlates with escape from X-chromosome inactivation of several key immune regulatory genes. In Drosophila females, mating and male Sex Peptide cause increased reproduction but also inflammation and shortened life span. We have shown that these effects can be reversed by feeding the human drug mifepristone/RU486, yielding +70% increase in median life span, and correlated with altered X-linked gene expression, metabolic re-programming, and altered microbiome. We will test the hypothesis that female reproductive metabolism makes mitochondria more susceptible to bacterial toxins, thereby reducing healthspan and life span. We test conserved genes and pathways, including catecholamine signaling, cholesterol metabolism, and the role of specific microbial metabolites. Methods include florescent transgenic reporter constructs, high- throughput sequencing of microbial genomes and fly transcriptomes, 3D video tracking of fly gene expression and behavior, and testing conserved genes and small molecules for ability to increase life span and reduce inflammation. AIM 1 investigates mechanisms including signaling pathway genes and small molecules. AIM 2 investigates metabolome regulation, and AIM 3 identifies the relevant microbe(s) and metabolites. If successful this research will identify mechanisms for female-specific aging that might be partly conserved in humans, and may identify promising genetic targets and drugs for sex- specific interventions in human inflammation and aging-related disease.

概括人类疾病中的性别偏见很常见，但潜在机制仍不清楚。女性相对于男性具有免疫优势，但自身免疫性疾病也较多和阿尔茨海默病。女性的免疫优势受到怀孕和与逃避几个关键免疫的 X 染色体失活有关调控基因。在雌性果蝇中，交配和雄性性肽导致增加繁殖，还有炎症和寿命缩短。我们已经证明这些通过喂食人类药物米非司酮/RU486可以逆转效应，收率+70% 中位寿命的增加，并与 X 连锁基因表达的改变相关，代谢重新编程和微生物组改变。我们将检验以下假设：女性生殖代谢使线粒体更容易受到细菌毒素的影响，从而缩短健康寿命和寿命。我们测试保守的基因和途径，包括儿茶酚胺信号传导、胆固醇代谢以及特定的作用微生物代谢产物。方法包括荧光转基因报告构建体、高微生物基因组和果蝇转录组的通量测序、3D 视频跟踪果蝇基因表达和行为，并测试保守基因和小分子延长寿命和减少炎症的能力。 AIM 1 研究机制包括信号通路基因和小分子。 AIM 2 研究代谢组监管，AIM 3 识别相关微生物和代谢物。如果成功这项研究将确定女性特有的衰老机制，该机制可能部分是由于在人类中保守，并可能确定有希望的遗传目标和性药物对人类炎症和衰老相关疾病的具体干预措施。