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.

Project Narrative Obesity in the elderly is serious concern, but the key mechanism of aging and age-related diseases associated with obesity are yet to be determined. Our recent study shows that microbiome metabolite, delta-valerobetaine (VB) is associated with obesity-related phenotypes, e.g., body mass index and fatty liver in humans. Based on available evidence, we propose this study to understand the role of VB in aging using a mouse model.