The impact of nutrients and nutrient-derived metabolites on bone metabolism is an underexplored area. An age- associated increase in the generation of toxic reactive oxygen species has been implicated in osteoporotic disease, and our central hypothesis is that nutrient-derived oxidation products in particular play a key pathogenic role. Our previous data demonstrate that the tryptophan breakdown product, kynurenine, acting through the aryl hydrocarbon receptor, has detrimental effects on bone mass. This metabolism of tryptophan to produce kynurenine is mediated by the enzyme indoleamine 2,3-dioxygenase (IDO), which can be induced by interferon and regulates the immune system. However, not all of the metabolites generated from IDO-mediated tryptophan breakdown are detrimental (e.g., NAD+, melatonin, and picolinic acid may be beneficial). Our goal is to characterize the physiologic effects of tissue-specific blockade of the IDO pathway and then to determine whether selective re-addition of specific tryptophan metabolites maximizes gains in bone mass. To accomplish these goals, we propose the following specific aims: (1) Test the hypothesis that tissue-specific knockout of IDO1 will prevent inflammation-related bone loss; and (2) Test the hypothesis that different tryptophan metabolites are predominantly anabolic or catabolic. This project will also synergize with the other projects included in this application looking at effects of these metabolites in aging muscle (Project 2), mitochondrial function and cell senescence (Project 3) and in terms of sex-specific effects (Project 4). These innovative studies, together with the other tightly integrated projects of the Program Project proposal should provide new therapeutic targets for improving musculoskeletal health and increasing healthspan.