Microbiome Metabolite Valerobetaine: Mechanisms in Aging

项目摘要 微生物组代谢物Valerobetaine：衰老机制 肥胖症在美国迅速增加，越来越多的研究表明，肥胖症加速了 衰老表型与线粒体功能障碍、营养感知、细胞间通讯和 炎症等特征。已知肠道微生物群与肥胖和衰老有关 表型，但机制仍不明确。我们最近发现一种微生物代谢物，德尔塔- Valerobetaine(VB)，扰乱肉碱依赖的线粒体脂肪酸代谢，导致 喂食西方饮食的年轻小鼠的肥胖。这一点特别令人感兴趣，因为肉碱功能障碍- 依赖性线粒体脂肪酸代谢随着年龄的增长而发生，这是许多与年龄相关的疾病的共同特征 疾病。此外，补充肉碱，主要是以生物可利用度更高的乙酰肉碱形式 (ALCAR)，已知可防止线粒体结构和功能随年龄增长而下降。这就提高了 VB微生物群的产生可能同时引起肥胖和线粒体老化 并拮抗肉碱或Alcar的有益作用。我们设计了这个高风险、高收益的方案 为了解决两个目标，确定VB是否促进老龄小鼠线粒体衰老表型和 检测VB是否拮抗肉碱(Alcar)对线粒体衰老的有利作用。研究是 设计了老年雌性和雄性小鼠的实验变量，分别用对照小鼠饲料和西式饲料 并与两性幼鼠的相同操作进行比较。主要结果衡量标准是 重点阐述了VB对线粒体功能和肉碱依赖脂肪酸代谢的影响。我们的目标是 在认识到多种因素导致线粒体和其他衰老表型的情况下开发的，以及 饮食和微生物组的影响不太可能局限于一种微生物组衍生的代谢物。具体地说，如果 肥胖和衰老是农业在提供高营养质量饲料方面取得成功的后果 和更丰富的必需氨基酸，包括赖氨酸，蛋氨酸和色氨酸，然后 VB特效将与其他特效同时出现。例如，维生素B来自一种甲基化形式的赖氨酸，它 可能被蛋氨酸增强，蛋氨酸是营养感应中的关键氨基酸之一。类似地，VB效果可以 与色氨酸的微生物组代谢产物共生，色氨酸与细胞间信号和 炎症，或与胰岛素抵抗有关的支链氨基酸代谢物。 由于这些可能性，这项研究设计了额外的炎症和 衰老，以及全球代谢组学和转录组分析，以测试与其他 饮食和微生物组相关的代谢物。这一结果将对老龄化和与年龄相关的问题产生持续的影响 通过提供关于微生物组代谢物的直接机制知识进行疾病研究 通过与肥胖有关的机制促进衰老表型。

Project Summary Microbiome Metabolite Valerobetaine: Mechanisms in Aging Obesity is increasing rapidly in the US and accumulating research shows that obesity accelerates the pace of aging phenotypes related to mitochondrial dysfunction, nutrient sensing, intercellular communication and inflammation and other characteristics. Intestinal microbiome is known to contribute to both obesity and aging phenotypes, but mechanisms remain poorly defined. We recently found that a microbiome metabolite, delta- valerobetaine (VB), disrupts carnitine-dependent mitochondrial fatty acid metabolism and causes increased adiposity in young mice fed a Western diet. This is especially of interest because dysfunction of carnitine- dependent mitochondrial fatty acid metabolism occurs with aging and is a common feature of many age-related diseases. Additionally, carnitine supplementation, mostly in the more bioavailable form of acetylcarnitine (ALCAR), is known to protect against age-related decline in mitochondrial structure and function. This raises the possibility that microbiome production of VB causes or contributes to both obesity and mitochondrial aging and antagonizes beneficial effects of carnitine or ALCAR. We have designed this high-risk, high-gain proposal to address two aims, to determine whether VB promotes a mitochondrial aging phenotype in old mice and to test whether VB antagonizes beneficial effects of carnitine (ALCAR) on mitochondrial aging. Studies are designed with experimental variations in old female and male mice with control mouse diet and Western diet and compared to the same manipulations in young mice of both sexes. Primary outcome measures are focused on VB effects on mitochondrial functions and carnitine-dependent fatty acid metabolism. The aims are developed with recognition that multiple factors contribute to mitochondrial and other aging phenotypes, and that diet and microbiome effects are unlikely to be limited to one microbiome-derived metabolite. Specifically, if adiposity and aging are consequences of agricultural successes in providing high nutritional quality feed stock and more abundant essential amino acids, including lysine, methionine and tryptophan, in the human diet, then VB effects will co-occur with other effects. For instance, VB is derived from a methylated form of lysine, which may be potentiated by methionine, one of the key amino acids in nutrient sensing. Similarly, VB effects may co-occur with microbiome metabolites of tryptophan which have been linked to intercellular signaling and inflammation, or branched chain amino acid metabolites which have been linked to insulin resistance. Because of these possibilities, the study is designed with additional measures of inflammation and senescence, along with global metabolomics and transcriptomics analyses to test for associations with other diet- and microbiome-linked metabolites. The results will have sustained impact on aging and age-related disease research by providing direct mechanistic knowledge about a microbiome metabolite which could promote an aging phenotype through a mechanism linked to obesity.