Sex-Specific Aging Mechanisms

总结 人类疾病中的性别偏见很常见，但潜在的机制仍不清楚。 女性相对于男性具有免疫优势，但自身免疫性疾病也更大 和老年痴呆症女性的免疫优势受到怀孕的调节， 与几种关键免疫缺陷病毒的X染色体失活逃逸相关 调节基因在果蝇雌性中，交配和雄性性肽引起增加 生殖，而且炎症和缩短寿命。我们已经证明， 通过喂服人类药物米非司酮/RU 486可以逆转这种影响，产生+70% 中位寿命延长，并与X连锁基因表达改变相关， 代谢重编程和改变的微生物组我们将检验这个假设， 女性生殖代谢使线粒体更容易受到细菌毒素的影响， 从而降低健康寿命和寿命。我们检测保守的基因和途径， 包括儿茶酚胺信号传导、胆固醇代谢和特异性 微生物代谢产物方法包括荧光素转基因报告构建体、高表达的荧光素酶、荧光素酶抑制剂、荧光素酶抑制剂。 微生物基因组和苍蝇转录组的通量测序，3D视频跟踪 苍蝇基因表达和行为，并测试保守的基因和小分子， 增加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研究代谢组学 调节，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， 在人类中是保守的，并且可能会发现有希望的遗传靶点和性药物- 对人类炎症和衰老相关疾病的具体干预措施。

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.