Microbiome Metabolite Valerobetaine: Mechanisms in Aging

微生物组代谢物戊甜菜碱：衰老机制

• 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
• 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

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.

项目总结