Veterans with fractures suffer from injury-associated pain as well as post-operative surgical pain. The occurrence of a fracture contributes to acute pain and is largely manifested by mechanical, inflammatory, and neuropathic components. The LEAP study of high-energy lower extremity trauma showed that acute pain, in the recovery period after severe trauma, is the single largest predictor of long-term chronic pain 5-10 years after injury. There are 2 main strategies to treat trauma-induced and post-surgical pain: opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). Neither drug class completely alleviates pain, and both have negative side effects. Opioids, beyond eliciting cognitive impairment, are commonly associated with tolerance and addiction. NSAIDs are commonly used in combination with opioids following thoracic/abdominal surgery but use of this drug class for fracture pain is discouraged in the U.S. due to negative effects on skeletal health and healing of the injured skeleton. It is unclear which drug class is less destructive to the bone repair process but prevention of nonunion is paramount in the treatment of fractures as it places additional burden on the patient and the healthcare system due to prolonged pain and disability. Therefore, identification of therapies which improve both the bone healing process and diminish the fracture-associated pain is warranted. Our recent data demonstrate that mRNA levels of Sirtuin-1 (Sirt1, an NAD+ class III histone deacetylase) are robustly elevated during fracture healing. Fracture healing is impaired with age, bone loss, inflammation, and with neurodegeneration. Importantly, Sirt1 improves all of these conditions; however, to our knowledge, with the exception of our studies, nobody has specifically examined the effects of Sirt1 on fracture repair. Here we show that pharmacological activation of Sirt1 by SRT1720 allows for improved fracture healing while reducing pain behaviors. Based on these observations we hypothesize that activation of Sirt1 in mesenchymal lineage cells and associated nervous system interactions will enhance bone healing and reduce pain in mice by regulating inflammation. The proposed work will test this hypothesis, and may provide evidence that pharmacologic activation of Sirt1 could serve both as a novel bone healing agent and post-fracture analgesic agent. In Aim 1, we will demonstrate that SRT1720 can improve bone healing and reduce pain behaviors and inflammation in mice, and determine which cells require Sirt1 activation by SRT1720 for successful bone healing, reduced pain behaviors, and reduced inflammation. In Aim 2, we will determine how SRT1720 treatment, mesenchymal lineage cells, and primary afferent sensory neurons (PANs) regulate inflammation, and we will examine the crosstalk between mesenchymal lineage cells and PANs. Successful accomplishment of these Aims will demonstrate the utility of using Sirt1 activators as novel bone healing and post-fracture anal...