Microbiome Metabolite Valerobetaine: Mechanisms in Aging

微生物组代谢物戊甜菜碱：衰老机制

基本信息

批准号：
10763615
负责人：
Young-Mi Go Kang
金额：
$ 43.04万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-30 至 2025-09-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10763615
关键词：
Acceleration Acetylcarnitine Address Adipose tissue Adverse effects Age Aging Agriculture Amino Acids Autopsy Biological Biological Assay Biological Availability Body fat Body mass index Branched-Chain Amino Acids Brown Fat C57BL/6 Mouse Carnitine Characteristics Data Development Diet Disease Drug or chemical Tissue Distribution Elderly Essential Amino Acids Fatty Liver Female Functional disorder Genetic Transcription Half-Life Health Human Impairment Inflammation Insulin Resistance Intervention Investments Kidney Knowledge Link Lysine Magnetic Resonance Imaging Measures Memory impairment Metabolic Methionine Methylation Mitochondria Modeling Monitor Mus N(6)-carboxymethyllysine Nutritional Obesity Obesity Epidemic Outcome Measure Phenotype Plasma Population Production Research Risk Risk Factors Role Sex Differences Signal Transduction Structure Testing Therapeutic Tissues Toxin Tryptophan Uremia Variant Visceral Weight acylcarnitine age related antagonist anti aging burden of illness carnitine supplementation comorbidity comparison control design detection of nutrient dietary dietary control experimental study fatty acid metabolism fatty acid oxidation fatty liver disease functional decline gut microbiome healthy aging high risk improved in vivo intercellular communication interest male metabolomics meter microbial microbiome mitochondrial dysfunction mouse model obesity management oxidation prevent primary outcome reuptake risk prediction senescence sex subcutaneous success transcriptome sequencing transcriptomics trimethyllysine western diet

项目摘要

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.

项目摘要微生物组代谢物瓣膜：衰老的机制在美国，肥胖症正在迅速增加，积累的研究表明肥胖可以加速与线粒体功能障碍，营养感应，细胞间通讯和炎症和其他特征。已知肠道微生物组有助于肥胖和衰老表型，但机制的定义仍然很差。最近，我们发现微生物组代谢产物Delta- Valerobetaine（VB），破坏肉碱依赖性的线粒体脂肪酸代谢，并导致增加年轻小鼠喂食西方饮食的肥胖。这尤其令人感兴趣，因为肉碱功能障碍 - 依赖性线粒体脂肪酸代谢随老化而发生，并且是许多年龄相关的常见特征疾病。另外，补充肉碱，主要是以更可生物利用的形式（Alcar）已知可以预防与年龄相关的线粒体结构和功能下降。这加剧了 VB原因的微生物组产生或导致肥胖和线粒体衰老的可能性并拮抗肉碱或阿尔卡的有益作用。我们设计了这个高风险，高获得的建议要解决两个目标，以确定VB是否促进了旧小鼠的线粒体衰老表型和测试VB是否拮抗肉碱（Alcar）对线粒体衰老的有益作用。研究是通过对照鼠标饮食和西方饮食的老雌性和雄性小鼠的实验变化设计并与两性年轻小鼠的同一操作相比。主要结果指标是侧重于VB对线粒体功能和carnitine依赖性脂肪酸代谢的影响。目的是认识到多种因素有助于线粒体和其他衰老表型，以及饮食和微生物组的影响不太可能仅限于一种微生物组来源的代谢产物。具体来说，如果肥胖和衰老是提供高营养质量饲料库存的农业成功的后果在人类饮食中，包括赖氨酸，蛋氨酸和色氨酸在内的更丰富的必需氨基酸，然后 VB效应将与其他效果共同发生。例如，Vb源自甲基化的赖氨酸的甲基化形式，该形式蛋氨酸可能会增强蛋氨酸，这是营养感应中的关键氨基酸之一。同样，VB效应可能与色氨酸的微生物组代谢物共发生，该代谢物已与细胞间信号和炎症或分支链氨基酸代谢产物与胰岛素抵抗有关。由于这些可能性，该研究的设计采用了其他炎症和衰老，以及全球代谢组学和转录组学分析，以测试与其他饮食和微生物组连接的代谢产物。结果将对衰老和年龄有关通过提供有关微生物组代谢产物的直接机械知识来研究的疾病研究通过与肥胖相关的机制来促进衰老表型。