PROJECT SUMMARY Persistent organic pollutants such as organophosphate flame retardants (OPFRs) can accumulate in the body and interact with nuclear receptors important in endocrine regulation. Given that OPFR exposure is pervasive in the human population, there is a critical need to determine the impact of long-term exposure to OPFRs on human health. Specifically, the impact of OPFR exposure on metabolic and brain aging remains undetermined. Recent studies showed that perinatal exposure to an OPFR, triphenyl phosphate (TPHP), led to exacerbated high fat diet-induced metabolic syndrome and gut dysbiosis. Notably, gut dysbiosis and the decrease in gut barrier function have been associated with augmentation of systemic inflammation, metabolic dysfunction, neuroinflammation and aging. Preliminary data from the lab showed an age-associated increase in facultative, pro-inflammatory Proteobacteria, an indicator of epithelial cell dysfunction. Consistently, preliminary data showed age-associated increases in gut permeability and systemic inflammation. Furthermore, using untargeted serum metabolomics, tryptophan metabolism was identified as a signature pathway associated with aging; remarkably, indole and indole-3-lactic acid, beneficial metabolites derived from the bacterial tryptophan catabolism pathway, were significantly decreased with age. In addition, there were age-associated decreases in fecal levels of butyric and propionic acids; these microbially produced short-chain fatty acids (SCFA) have been shown to improve glucose homeostasis and insulin sensitivity. Importantly, new preliminary data suggested that acute TPHP exposure in young adult mice exerted deleterious effects on colon epithelial cells, with impaired barrier function and shifts in metabolism that favors colonization of facultative, pathogenic bacteria. Together, these data provide a strong scientific premise for studying long-term effects of TPHP on the microbiome-gut-brain axis in aging. The central hypothesis is that exposure to TPHP induces gut dysbiosis, leading to gut barrier dysfunction, systemic inflammation, and neuroinflammation; these inflammatory pathologies exacerbate aging-associated metabolic and cognitive decline. This exploratory hypothesis will be tested by pursuing the following aim: Define the extent to which TPHP exposure contributes to metabolic and cognitive decline. An aging cohort will be used, starting TPHP exposure from 10 months (M) of age as a mid-life exposure model. Fecal microbiome, metabolome at 10, 15 and 18 M, in vivo metabolic and cognitive function at 13-15 M will be assessed in sub-Aim A, and, using these mice as donor mice, the causality of dysbiotic microbiota induced by TPHP exposure in exacerbating metabolic and brain aging will be mechanistically tested via fecal microbiota transplantation experiments in sub-Aim B. Senescence phenotypes in colon, liver, and brain will be characterized in sub-Aim C. Overall, results will demonstrate the contri...