Sex-Specific Aging Mechanisms

摘要 性别偏见在人类疾病中很常见，但潜在的机制仍不清楚。 女性比男性有免疫优势，但也有更大的自身免疫性疾病 和阿尔茨海默氏症。女性的免疫优势受怀孕和 与逃脱X染色体失活的几种关键免疫相关 调控基因。在雌性果蝇中，交配和雄性性肽引起的增加 但生殖也会发炎，寿命缩短。我们已经证明，这些 通过给人类药物米非司酮/RU486喂食，效果可以逆转，产量+70% 中位寿命的延长，并与X连锁基因表达的变化相关， 新陈代谢重新编程，改变了微生物群。我们将检验这一假设 雌性生殖新陈代谢使线粒体更容易受到细菌毒素的影响， 从而降低健康寿命和寿命。我们测试保守的基因和途径， 包括儿茶酚胺信号转导、胆固醇代谢和特异性作用 微生物代谢物。方法包括荧光转基因报告构建，高密度 微生物基因组和苍蝇转录体的吞吐量测序，3D视频跟踪 苍蝇的基因表达和行为，以及测试保守的基因和小分子 能够延长寿命和减少炎症。目标1研究机制 包括信号通路基因和小分子。AIM 2研究代谢组 调控，AIM 3确定相关微生物(S)和代谢物。如果成功 这项研究将确定女性特有的衰老机制，这可能是 在人类中保存，并可能识别有希望的基因靶点和性行为药物- 对人类炎症和衰老相关疾病的具体干预。

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.